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Hale, Karin K., David Trollinger, Marynette Rihanek, and Carl L. Manthey. "Differential Expression and Activation of p38 Mitogen-Activated Protein Kinase α, β, γ, and δ in Inflammatory Cell Lineages." Journal of Immunology 162, no. 7 (April 1, 1999): 4246–52. http://dx.doi.org/10.4049/jimmunol.162.7.4246.
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Abstract Four p38 mitogen-activated protein kinases (p38α, β, γ, δ) have been described. To understand the role of p38 family members in inflammation, we determined their relative expression in cells that participate in the inflammatory process. Expression was measured at the level of mRNA by reverse-transcriptase PCR and protein by Western blot analysis. p38α was the dominant form of p38 in monocytes; expression of p38δ was low and p38β was undetected. In macrophages, p38α and p38δ were abundant, but p38β was undetected. p38α and p38δ were also expressed by neutrophils, CD4+ T cells, and endothelial cells. Again, p38β was not detected in neutrophils, although low amounts were present in CD4+ T cells. In contrast, p38β was abundant in endothelial cells. p38γ protein was not detected in any cell type, although p38γ mRNA was present in endothelial cells. Immunokinase assays showed a strong activation of p38α and a lesser activation of p38δ in LPS-stimulated macrophages. Abs specific for mono- and dual-phophorylated forms of p38 suggested that LPS induces dual phosphorylation of p38α, but primarily mono-phosphorylation of p38δ. IL-1β activated p38α and p38β in endothelial cells. However, p38α was the more activated form based on kinase assays and phosphorylation analysis. Expression and activation patterns of p38α in macrophages and endothelial cells suggest that p38α plays a major role in the inflammatory response. Additional studies will be needed to define the contribution of p38δ to macrophage, neutrophil, and T cell functions, and of p38β to signaling in endothelial cells and T cells.
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Risco, Ana, and Ana Cuenda. "New Insights into the p38γ and p38δ MAPK Pathways." Journal of Signal Transduction 2012 (November 30, 2012): 1–8. http://dx.doi.org/10.1155/2012/520289.
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The mammalian p38 mitogen-activated protein kinases (MAPKs) family is composed of four members (p38α, p38β, p38γ, and p38δ), which are very similar in amino acid sequence but differ in their expression patterns. This suggests that they may have specific functions in different organs. In the last years most of the effort has been centred on the study of the function of the p38α isoform, which is widely referred to as p38 in the literature. However, the role that other p38 isoforms play in cellular functions and their implication in some of the pathological conditions have not been precisely defined so far. In this paper we highlight recent advances made in defining the functions of the two less studied alternative p38MAPKs, p38γ and p38δ. We describe that these p38MAPKs show similarities to the classical p38α isoform, although they may play central and distinct role in certain physiological and pathological processes.
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Adachi-Yamada, Takashi, Makoto Nakamura, Kenji Irie, Yoshinori Tomoyasu, Yorikata Sano, Eiji Mori, Satoshi Goto, Naoto Ueno, Yasuyoshi Nishida, and Kunihiro Matsumoto. "p38 Mitogen-Activated Protein Kinase Can Be Involved in Transforming Growth Factor β Superfamily Signal Transduction in Drosophila Wing Morphogenesis." Molecular and Cellular Biology 19, no. 3 (March 1, 1999): 2322–29. http://dx.doi.org/10.1128/mcb.19.3.2322.
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ABSTRACT p38 mitogen-activated protein kinase (p38) has been extensively studied as a stress-responsive kinase, but its role in development remains unknown. The fruit fly, Drosophila melanogaster, has two p38 genes, D-p38a and D-p38b. To elucidate the developmental function of the Drosophilap38’s, we used various genetic and pharmacological manipulations to interfere with their functions: expression of a dominant-negative form of D-p38b, expression of antisense D-p38b RNA, reduction of theD-p38 gene dosage, and treatment with the p38 inhibitor SB203580. Expression of a dominant-negative D-p38b in the wing imaginal disc caused a decapentaplegic (dpp)-like phenotype and enhanced the phenotype of a dpp mutant. Dpp is a secretory ligand belonging to the transforming growth factor β superfamily which triggers various morphogenetic processes through interaction with the receptor Thick veins (Tkv). Inhibition of D-p38b function also caused the suppression of the wing phenotype induced by constitutively active Tkv (TkvCA). Mosaic analysis revealed that D-p38b regulates the Tkv-dependent transcription of theoptomotor-blind (omb) gene in non-Dpp-producing cells, indicating that the site of D-p38b action is downstream of Tkv. Furthermore, forced expression of TkvCA induced an increase in the phosphorylated active form(s) of D-p38(s). These results demonstrate that p38, in addition to its role as a transducer of emergency stress signaling, may function to modulate Dpp signaling.
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Xing, Feiyue, Yong Jiang, Jing Liu, Kesen Zhao, Yongyan Mo, Zhifeng Liu, and Yaoying Zeng. "Downregulation of human endothelial nitric oxide synthase promoter activity by p38 mitogen-activated protein kinase activation." Biochemistry and Cell Biology 84, no. 5 (October 2006): 780–89. http://dx.doi.org/10.1139/o06-092.
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Human endothelial nitric oxide synthase (eNOS) plays a crucial role in maintaining blood pressure homeostasis and vascular integrity. eNOS gene expression may be upregulated by a signaling pathway, including PI-3Kγ → Jak2 → MEK1 → ERK1/2 → PP2A. It remains unclear whether other mitogen-activated protein kinase (MAPK) family members, such as JNK, p38 kinase, and ERK5/BMK1, also modulate eNOS gene expression. Our purpose, therefore, is to shed light on the effect of the p38 MAPK signaling pathway on the regulation of eNOS promoter activity. The results showed that a red fluorescent protein reporter gene vector containing the full length of the human eNOS promoter was first successfully constructed, expressing efficiently in ECV304 cells with the characteristics of real time observation. The wild-types of p38α, p38β, p38γ, and p38δ signal molecules all markedly downregulated promoter activity, which could be reversed by their negative mutants, including p38α (AF), p38β (AF), p38γ (AF), and p38δ (AF). Promoter activity was also significantly downregulated by MKK6b (E), an active mutant of an upstream kinase of p38 MAPK. The reduction in promoter activity by p38 MAPK could be blocked by treatment with a p38 MAPK specific inhibitor, SB203580. Moreover, the activation of endogenous p38 MAPK induced by lipopolysaccharide resulted in a prominent reduction in promoter activity. These findings strongly suggest that the activation of the p38 MAPK signaling pathway may be implicated in the downregulation of human eNOS promoter activity.
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Roche, Olga, Diego M. Fernández-Aroca, Elena Arconada-Luque, Natalia García-Flores, Liliana F. Mellor, María José Ruiz-Hidalgo, and Ricardo Sánchez-Prieto. "p38β and Cancer: The Beginning of the Road." International Journal of Molecular Sciences 21, no. 20 (October 12, 2020): 7524. http://dx.doi.org/10.3390/ijms21207524.
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The p38 mitogen-activated protein kinase (MAPK) signaling pathway is implicated in cancer biology and has been widely studied over the past two decades as a potential therapeutic target. Most of the biological and pathological implications of p38MAPK signaling are often associated with p38α (MAPK14). Recently, several members of the p38 family, including p38γ and p38δ, have been shown to play a crucial role in several pathologies including cancer. However, the specific role of p38β (MAPK11) in cancer is still elusive, and further investigation is needed. Here, we summarize what is currently known about the role of p38β in different types of tumors and its putative implication in cancer therapy. All evidence suggests that p38β might be a key player in cancer development, and could be an important therapeutic target in several pathologies, including cancer.
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Gonzalez, Maria E., Shilpa R. Tekula, Talha Anwar, Shoshana A. Leflein, and Celina G. Kleer. "Abstract PD3-03: EZH2 T367 phosphorylation activates p38 signaling through lysine methylation to promote breast cancer progression." Cancer Research 82, no. 4_Supplement (February 15, 2022): PD3–03—PD3–03. http://dx.doi.org/10.1158/1538-7445.sabcs21-pd3-03.
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Abstract Introduction: Triple negative breast cancers (TNBC) are frequently poorly differentiated with higher propensity for metastasis than all other subtypes. Enhancer of Zeste Homolog 2 (EZH2) is a lysine methyltransferase that mediates transcriptional repression of pro-differentiation genes in normal and neoplastic cells. The oncogenic role of EZH2 through H3K27me3 is well established. However, non-canonical H3K27me3-independent functions are unclear. We have reported that p38 phosphorylates T367 of EZH2, increasing TNBC metastasis. Recent reports show that EZH2 can regulate signaling pathways through direct methylation of proteins suggesting the hypothesis that EZH2 may methylate p38 in TNBC. Methods: Human tissue samples from 16 primary invasive breast carcinomas and matched distant metastasis arrayed in tissue microarrays were interrogated for pEZH2 T367 and p-p38 by immunohistochemistry. To study p38 methylation, we performed LC-MS/MS analyses GST-p38α, and GST-EZH2 were each incubated with or without recombinant PRC2 complex (EZH2/E ED/SUZ12/RbAp48/AEBP2) and S-adenosyl methionine methyl donor. MDA-MB-231, mouse and human primary TNBC cells and murine 4T1 cells were used in funcional assays in vitro and in vivo. EZH2 knockdown and rescue was carried out using lentiviral transduction of EZH2 with pBabe-myc-EZH2 (wild-type) or pBabe-myc-EZH2 (T367A). We developed p38 methylation mutants: HA-p38a K139A, HA-p38a K165A, and HA-p38a K130A/K165K. To investigate the importance of EZH2 and p38 enzymatic activities we used the EZH2 methyltransferase inhibitors GSK-343 and EPZ-6438 and the p38 inhibitor SB202190 in vitro and in vivo. For animal studies, MDA-MB-231 and 4T1 cells were orthotopically injected into the right inguinal mammary fat pad of eight-week old NOD/SCID or BALBc mice, respectively. When tumors reached 100 mm3 mice were treated 5 days/week by intraperitoneal injection with SB202190 (1mg/kg/day), EPZ-6438 (10mg/kg/day), combination of SB202190 and EPZ-6438, or control. We monitored tumor growth for 50 days, and harvested primary tumors, lungs, and sites of metastasis for histopathology, Western blot, and immunohistochemistry. Primary xenografts from the control and treatment groups were subjected to RNA sequencing. Results: EZH2 methylates p38 at lysines 139 and 165 leading to enhanced p38 stability and increased invasion, and p38 activation requires T367 phosphorylation of EZH2. Dual inhibition of EZH2 methyltransferase and p38 kinase activities downregulates pEZH2 T367, H3K27me3, and p-p38 in vivo, reduces TNBC growth and metastasis, and results in gene expression changes towards a better differentiated phenotype. pEZH2 T367 and p-p38 proteins are significantly coexpressed in human primary and metastatic breast cancer. Conclusions: We provide direct evidence that EZH2 methylates p38 with resultant p38 activation, and that EZH2 phosphorylation at T367 is important for this function. Dual targeting of EZH2 methyltransferase and p38 kinase activities with specific inhibitors reduces breast cancer growth and metastasis indicating a cooperation between EZH2 canonical and non-canonical mechanisms and suggesting therapeutic strategies. Citation Format: Maria E Gonzalez, Shilpa R. Tekula, Talha Anwar, Shoshana A. Leflein, Celina G. Kleer. EZH2 T367 phosphorylation activates p38 signaling through lysine methylation to promote breast cancer progression [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD3-03.
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Gutierrez-Sanmartin, Dolores, Eduardo Varela-Ledo, Antonio Aguilera, Susana Romero-Yuste, Patricia Romero-Jung, Antonio Gomez-Tato, and Benito J. Regueiro. "Implication of p38 mitogen-activated protein kinase isoforms (α, β, γ and δ) in CD4+ T-cell infection with human immunodeficiency virus type I." Journal of General Virology 89, no. 7 (July 1, 2008): 1661–71. http://dx.doi.org/10.1099/vir.0.82971-0.
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The CD4+ T-cell reduction characteristic of human immunodeficiency virus type 1 (HIV-1) infection is thought to result, in addition to infected T-cell death, mainly from uninfected bystander T-cell apoptosis. Nevertheless, the immunological and virological mechanisms leading to T-cell death during HIV-1 infection are not yet fully understood. In the present study, we analysed the individual implication of the p38 mitogen-activated protein kinase (MAPK) isoforms (p38α, p38β, p38γ and p38δ) during apoptosis induced by HIV-1, taking into account that HIV-1 replication is known to be blocked by p38 inhibitors. For this purpose, we used the SupT1 cell line, where death induced by HIV-1 mainly occurs by uninfected bystander cell apoptosis. A variety of SupT1-based cell lines were constructed constitutively expressing, under the control of cytomegalovirus promoter (PCMV), each dominant-negative (dn) p38 isoform and each wild-type p38 isoform as a control. An enhanced green fluorescent protein marker gene, under the control of the HIV-1 promoter, was inserted in all of them. These cell lines were infected with HIV-1 and analysed by flow cytometry. We found that survival in SupT1-based cell lines infected by HIV-1 was increased by the p38αdn, p38γdn and p38δdn isoforms, but not by the p38βdn isoform. HIV-1 replication was delayed most by p38δdn and to a lesser extent by p38αdn and p38γdn. Moreover, these three isoforms, p38αdn, p38γdn and p38δdn, reduced apoptosis induced by HIV-1. These results suggest that, in SupT1-based cell lines, p38α, p38γ and p38δ, but not p38β, are implicated in both HIV-1 induced replication and apoptosis in infected and uninfected bystander cells.
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KUMA, Yvonne, David G. CAMPBELL, and Ana CUENDA. "Identification of glycogen synthase as a new substrate for stress-activated protein kinase 2b/p38beta." Biochemical Journal 379, no. 1 (April 1, 2004): 133–39. http://dx.doi.org/10.1042/bj20031559.
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The endogenous glycogen synthase in extracts from mouse skeletal muscle, liver and brain bound specifically to SAPK2b (stress-activated protein kinase 2b)/p38β, but not to other members of the group of SAPK/p38 kinases. Glycogen synthase was phosphorylated in vitro more efficiently by SAPK2b/p38β than by SAPK2a/p38α, SAPK3/p38γ or SAPK4/p38δ. SAPK2b/p38β phosphorylated glycogen synthase in vitro at residues Ser644, Ser652, Thr718 and Ser724, two of which (Ser644 and Ser652) are also phosphorylated by glycogen synthase kinase 3. Thr718 and Ser724 are novel sites not known to be phosphorylated by other protein kinases. Glycogen synthase becomes phosphorylated at Ser644 in response to osmotic shock; this phosphorylation is prevented by pretreatment of the cells with SB 203580, which inhibits SAPK2a/p38α and SAPK2b/p38β activity. In vitro, phosphorylation of glycogen synthase by SAPK2b/p38β alone had no significant effect on its activity, indicating that phosphorylation at residue Ser644 itself is insufficient to decrease glycogen synthase activity. However, after phosphorylation by SAPK2b/p38β, subsequent phosphorylation at Ser640 by glycogen synthase kinase 3 decreased the activity of glycogen synthase. This decrease was not observed when SAPK2b/p38β activity was blocked with SB 203580. These results suggest that SAPK2b/p38β may be a priming kinase that allows glycogen synthase kinase 3 to phosphorylate Ser640 and thereby inhibit glycogen synthase activity.
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Thouverey, Cyril, and Joseph Caverzasio. "Ablation of p38α MAPK Signaling in Osteoblast Lineage Cells Protects Mice From Bone Loss Induced by Estrogen Deficiency." Endocrinology 156, no. 12 (October 6, 2015): 4377–87. http://dx.doi.org/10.1210/en.2015-1669.
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Estrogen deficiency causes bone loss by increasing the number of bone-resorbing osteoclasts. Selective p38α MAPK inhibitors prevent bone-wasting effects of estrogen withdrawal but implicated mechanisms remain to be identified. Here, we show that inactivation of the p38α-encoding gene in osteoblast lineage cells with the use of an osteocalcin-cre transgene protects mice from ovariectomy-induced bone loss (a murine model of postmenopausal osteoporosis). Ovariectomy fails to induce bone loss, increase bone resorption, and stimulate receptor activator of nuclear factor κB ligand and IL-6 expression in mice lacking p38α in osteoblasts and osteocytes. Finally, TNFα or IL-1, which are osteoclastogenic cytokines overproduced in the bone marrow under estrogen deficiency, can activate p38α signaling in osteoblasts, but those cytokines cannot enhance Rankl and Il6 expressions or increase osteoclast formation in p38a-deficient osteoblast cultures. These findings demonstrate that p38α MAPK signaling in osteoblast lineage cells mediates ovariectomy-induced bone loss by up-regulating receptor activator of nuclear factor κB ligand and IL-6 production.
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Lovett, Fiona A., Ruth A. Cosgrove, Ivelisse Gonzalez, and Jennifer M. Pell. "Essential Role for p38α MAPK But Not p38γ MAPK in Igf2 Expression and Myoblast Differentiation." Endocrinology 151, no. 9 (July 7, 2010): 4368–80. http://dx.doi.org/10.1210/en.2010-0209.
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The muscle satellite cell is established as the major stem cell contributing to fiber growth and repair. p38 MAPK signaling is essential for myoblast differentiation and in particular for up-regulation of promyogenic Igf2 expression. p38 exists as four isoforms (α, β, γ, and δ), of which p38γ is uniquely abundant in muscle. The aim of this study was to characterize p38 isoform expression and importance (using shRNA knockdown; demonstrated via both reduced protein and kinase activities) during myoblast differentiation. p38α and -γ mRNA levels were most abundant in differentiating C2 cells with low/negligible contributions from p38β and -δ, respectively. Increased phosphorylation of p38α and -γ occurred during differentiation but via different mechanisms: p38α protein levels remained constant, whereas total p38γ levels increased. Following shRNA knockdown of p38α, myoblast differentiation was dramatically inhibited [reduced myosin heavy chain (MHC), myogenin, pAkt protein levels]; significantly, Igf2 mRNA levels and promoter-reporter activities decreased. In contrast, knockdown of p38γ induced a transient increase in both myogenin and MHC protein levels with no effect on Igf2 mRNA levels or promoter-reporter activity. Knockdown of p38α/β markedly increased but that of p38γ decreased caspase 3 activity, suggesting opposite actions on apoptosis. p38γ was initially proposed to have a promyogenic function; however, p38γ overexpression could not rescue reduced myoblast differentiation following p38α/β inhibition. Therefore, p38α is essential for myoblast differentiation, and part of its action is to convert signals that indicate cell density into promyogenic gene expression in the form of the key peptide, IGF-II; p38γ has a minor, yet opposing antimyogenic, function.
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De Nicola, G. F., R. Bassi, E. V. Martin, M. Caggiano Fernandez, C. Nichols, R. Anderson, D. Thapa, J. Clark, and M. S. Marber. "59The TAB1-p38a complex is a therapeutic target in acute myocardial ischemia: the holy grail of circumstance selective inhibition of p38a." Cardiovascular Research 114, suppl_1 (April 1, 2018): S15. http://dx.doi.org/10.1093/cvr/cvy060.025.
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Matrone, A. "405 p38a is required for cancer-specific metabolism and survival." European Journal of Cancer Supplements 8, no. 5 (June 2010): 104. http://dx.doi.org/10.1016/s1359-6349(10)71206-4.
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Beardmore, Victoria A., Heather J. Hinton, Christina Eftychi, Maria Apostolaki, Maria Armaka, Joanne Darragh, Joanne McIlrath, et al. "Generation and Characterization of p38β (MAPK11) Gene-Targeted Mice." Molecular and Cellular Biology 25, no. 23 (December 1, 2005): 10454–64. http://dx.doi.org/10.1128/mcb.25.23.10454-10464.2005.
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ABSTRACT p38 mitogen-activated protein kinases (MAPKs) are activated primarily in response to inflammatory cytokines and cellular stress, and inhibitors which target the p38α and p38β MAPKs have shown potential for the treatment of inflammatory disease. Here we report the generation and initial characterization of a knockout of the p38β (MAPK11) gene. p38β −/− mice were viable and exhibited no apparent health problems. The expression and activation of p38α, ERK1/2, and JNK in response to cellular stress was normal in embryonic fibroblasts from p38β−/− mice, as was the activation of p38-activated kinases MAPKAP-K2 and MSK1. The transcription of p38-dependent immediate-early genes was also not affected by the knockout of p38β, suggesting that p38α is the predominant isoform involved in these processes. The p38β −/− mice also showed normal T-cell development. Lipopolysaccharide-induced cytokine production was also normal in the p38β −/− mice. As p38 is activated by tumor necrosis factor, the p38β −/− mice were crossed onto a TNFΔARE mouse line. These mice overexpress tumor necrosis factor, which results in development symptoms similar to rheumatoid arthritis and inflammatory bowel disease. The progression of these diseases was not however moderated by knockout of p38β. Together these results suggest that p38α, and not p38β, is the major p38 isoform involved in the immune response and that it would not be necessary to retain activity against p38β during the development of p38 inhibitors.
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Navas, Tony A., Aaron N. Nguyen, Jing Y. Ma, Elizabeth G. Stebbins, Edwin Haghnazari, Ruth Heaton, Alan F. List, and Linda S. Higgins. "Inhibition of p38 MAPK by SCIO-469 Suppresses TNF Generation and Promotes CD34+ Cell Survival in an In Vitro MDS Cell Culture Model." Blood 104, no. 11 (November 16, 2004): 3424. http://dx.doi.org/10.1182/blood.v104.11.3424.3424.
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Abstract Progress in the development of more effective therapeutics for myelodysplastic syndrome (MDS) has been limited by the lack of targets critical to the pathobiology of the disease. Ineffective hematopoiesis in MDS is characterized by accelerated proliferation and premature apoptotic death of progenitors and their progeny that is potentiated by the local generation of inhibitory molecules, including TNFa, TGFß, FasL, and VEGF. To identify upstream regulatory signals that may coordinate activation of inhibitory molecules, we used an in vitro cell culture model incorporating a CD34+ MDS cell line isolated from a RAEB-t patient, normal bone marrow stromal cells (BMSC), and/ or bone marrow mononuclear cells (BMMNC) to determine effects of cell-cell interactions on secretion of inhibitory hematopoietic cytokines. The role of p38 MAP kinase, a regulatory kinase involved in the convergence of inhibitory cytokine activation and signaling, was evaluated in this interaction. We found that p38 MAPK is induced under basal culture conditions in the MDS cell line and is further activated by TNFa or TGFß. In all cases, p38 activation was reduced by SCIO-469, a potent and specific inhibitor of p38a activity. SCIO-469 does not directly block p38 activation, suggesting a feedback loop is interrupted when p38 kinase activity is inhibited in MDS cells. To determine the effects of cellular interactions, the MDS cell line was co-cultured with either BMSC, BMMNCs or both from normal donors, and TNFa and FasL secretion were measured after 3 days incubation. TNFa and FasL were detected in culture supernatants when the MDS cell line was co-cultured with BMMNC but not when co-cultured with BMSC. TNFa secretion by BMMNCs was dependent on MDS cell contact and was significantly inhibited by SCIO-469. The addition of BMSC to the MDS and BMMNC co-culture prevented TNFa elevation, suggesting BMSCs as a dominant source for anti-inflammatory signal(s). VEGF, FGF-ß, TGFß2, BDNF, TIMP-1, TIMP-2 and IL-6 secretion by BMSC was induced by MDS co-culture, whereas SCIO-469 blocked cytokine induction. To determine the effects of SCIO-469 and MDS clone-induced BM cytokine secretion on normal CD34+ proliferation, we co-cultured BMMNCs and BMSC in transwell inserts in the presence or absence of the MDS cell line with or without SCIO-469. CD34+ proliferation was assessed in cells cultured in outer wells. CD34+ progenitors proliferated in culture at the same rate as those co-cultured with BMSC, BMMNC and MDS for 6 days. At longer intervals, viability of progenitors cultured with the MDS line declined, whereas treatment with SCIO-469 abrogated the decrease in CD34+ viability. These results implicate p38a as a critical target in the induction of pro-apoptotic cytokines in MDS, and that selective inhibition of p38 by SCIO-469 may provide a novel therapeutic strategy for MDS.
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New, Liguo, Yong Jiang, and Jiahuai Han. "Regulation of PRAK Subcellular Location by p38 MAP Kinases." Molecular Biology of the Cell 14, no. 6 (June 2003): 2603–16. http://dx.doi.org/10.1091/mbc.e02-08-0538.
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The p38 mitogen-activated protein kinase (MAPK) pathway plays an important role in cellular responses to inflammatory stimuli and environmental stress. p38 regulated/activated protein kinase (PRAK, also known as mitogen-activated protein kinase activated protein kinase 5 [MAPKAPK5]) functions downstream of p38α and p38β in mediating the signaling of the p38 pathway. Immunostaining revealed that endogenous PRAK was predominantly localized in the cytoplasm. Interestingly, ectopically expressed PRAK was localized in the nucleus and can be redistributed by coexpression of p38α or p38β to the locations of p38α and p38β. Mutations in the docking groove on p38α/p38β, or the p38-docking site in PRAK, disrupted the PRAK-p38 interaction and impaired the ability of p38α and p38β to redistribute ectopically expressed PRAK, indicating that the location of PRAK could be controlled by its docking interaction with p38α and p38β. Although the majority of PRAK molecules were detected in the cytoplasm, PRAK is consistently shuttling between the cytoplasm and the nucleus. A sequence analysis of PRAK shows that PRAK contains both a putative nuclear export sequence (NES) and a nuclear localization sequence (NLS). The shuttling of PRAK requires NES and NLS motifs in PRAK and can be regulated through cellular activation induced by stress stimuli. The nuclear content of PRAK was reduced after stimulation, which resulted from a decrease in the nuclear import of PRAK and an increase in the nuclear export of PRAK. The nuclear import of PRAK is independent from p38 activation, but the nuclear export requires p38-mediated phosphorylation of PRAK. Thus, the subcellular distribution of PRAK is determined by multiple factors including its own NES and NLS, docking interactions between PRAK and docking proteins, phosphorylation of PRAK, and cellular activation status. The p38 MAPKs not only regulate PRAK activity and PRAK activation-related translocation, but also dock PRAK to selected subcellular locations in resting cells.
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Takubo, Keiyo, Yukako Ootomo, and Daiki Karigane. "p38a protects hematopoietic stem cells from physiological and premature aging stresses." Experimental Hematology 53 (September 2017): S64. http://dx.doi.org/10.1016/j.exphem.2017.06.116.
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Zhang, Xu Hannah, Christiane Querfeld, and Steven T. Rosen. "Dissecting the Roles of p38β and p38γ in Cutaneous T Cell Lymphoma." Blood 132, Supplement 1 (November 29, 2018): 2866. http://dx.doi.org/10.1182/blood-2018-99-118992.
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Abstract Cutaneous T cell lymphoma (CTCL) is a disfiguring, incurable cancer that develops from clonal expansion of T cells and most commonly presents on the skin. For patients with advanced disease, current therapies are inadequate, and outcome is poor. An incomplete understanding of CTCL molecular regulators has limited development of effective targeted therapies. One candidate molecular regulator is p38γ, a mitogen-activated protein kinase (MAPK) crucial for malignant T cell activity and growth in response to T cell receptor (TCR) signaling. We previously reported that p38β (Bliss-Moreau, JID, 2014) and p38γ (Zhang, JID, 2018) are promising therapeutic targets for CTCL. We examined both RNA-seq and microarray public databases for gene expression and found that both targets are elevated in CTCL cell lines and patient samples, compared to normal T cells. This is consistent with literature showing that in several organs of the healthy human immune system, although p38α and p38δ isoforms are highly expressed, p38β and p38γ are typically very low (Wang, JBC, 1997). We demonstrated that knockdown of p38γ, but not p38β, causes cell death in the human CTCL cell line Hut78. In addition, overexpression of either target causes proliferation in CTCL cells. In this study, we dissected the roles of both p38β and p38γ in CTCL and delineated their downstream pathways. DLGH1 is an important scaffolding protein that directs T-cell signaling through the nuclear factor of activated T-cells (NFAT) pathway rather than through the NF-κB pathway (Round, Nat Immunol, 2007; Sabio, EMBO J, 2005). Our recent data indicate that knockdown of p38β reduced expression of DLGH1 at both the mRNA and protein level, but upregulated gene expression of CARMA1, which directs TCR signaling to the NF-kB pathway (Thome and Tschopp, Trends in Immunology, 2003). p38γ directly phosphorylates DLGH1 at ser158 in Hut78 cells (Sabio, EMBO J, 2005; Zhang, JID, 2018). We showed that inhibition of this phosphorylation reduced the role of both NFAT and NF-kB signaling in regulation of the immune response. Thus, our data indicate that DLGH1 is a common target of both p38β and p38γ isoforms. In addition, curcumin treatment causes induction of both p38γ and DLGH1 protein expression, but causes their reduction in p38β-knockdown Hut78 cells. This suggests an important role for p38β in TCR signaling via DLGH1 and its possible crosstalk with p38γ. We performed confocal microscopy of immunofluorescent p-p38 Tyr323 staining in p38β-knockdown Hut78 cells, which revealed a "ring-like" structure formed in the cytosol, in contrast to a polarized structure in wild-type Hut78 cells. This suggests that loss of p38β abolishes initiation of TCR complex formation in the plasma membrane of Hut78 cells. It is reported that TCR signaling can be modulated by the actin cytoskeleton (Yu, J Cell Sci, 2013); we further pursued its potential mechanisms and found that loss of p38β reduced F-actin expression in Hut78 cells. However, that p38β modulates with cytoskeletal structure in malignant T cells via altered actin expression remains further investigation. In summary, DLGH1 is a common target of p38γ and p38β, which is involved in regulation of TCR signaling through either phosphorylation or downregulation of its protein expression by these two MAPK isoforms. Furthermore, DLGH1 provides a potential pathway for modulation of the T cell cytoskeleton by MAPKs and through which the downstream NFAT and NFkB pathways maybe directed. This opens new possibilities for the development of targeted therapies for CTCL. Disclosures Querfeld: Trillium Therapeutics: Membership on an entity's Board of Directors or advisory committees; Medivir: Membership on an entity's Board of Directors or advisory committees; Bioniz: Membership on an entity's Board of Directors or advisory committees; Kyowa: Membership on an entity's Board of Directors or advisory committees; Acelion: Membership on an entity's Board of Directors or advisory committees.
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Aenlle, Kristina K., Kevin M. Curtis, Bernard A. Roos, and Guy A. Howard. "Hepatocyte Growth Factor and p38 Promote Osteogenic Differentiation of Human Mesenchymal Stem Cells." Molecular Endocrinology 28, no. 5 (May 1, 2014): 722–30. http://dx.doi.org/10.1210/me.2013-1286.
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Abstract Hepatocyte growth factor (HGF) is a paracrine factor involved in organogenesis, tissue repair, and wound healing. We report here that HGF promotes osteogenic differentiation through the transcription of key osteogenic markers, including osteocalcin, osterix, and osteoprotegerin in human mesenchymal stem cells and is a necessary component for the establishment of osteoblast mineralization. Blocking endogenous HGF using PHA665752, a c-Met inhibitor (the HGF receptor), or an HGF-neutralizing antibody attenuates mineralization, and PHA665752 markedly reduced alkaline phosphatase activity. Moreover, we report that HGF promotion of osteogenic differentiation involves the rapid phosphorylation of p38 and differential regulation of its isoforms, p38α and p38β. Western blot analysis revealed a significantly increased level of p38α and p38β protein, and reverse transcription quantitative PCR revealed that HGF increased the transcriptional level of both p38α and p38β. Using small interfering RNA to reduce the transcription of p38α and p38β, we saw differential roles for p38α and p38β on the HGF-induced expression of key osteogenic markers. In summary, our data demonstrate the importance of p38 signaling in HGF regulation of osteogenic differentiation.
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Bassi, R., O. Rudyk, J. Burgoyne, P. Eaton, and M. S. Marber. "3 Can Redox-Sensitive Cysteines in P38A-MAPK Modulate Activation During Stress?" Heart 100, Suppl 1 (January 1, 2014): A2.3—A2. http://dx.doi.org/10.1136/heartjnl-2013-305297.3.
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Fearns, C., L. Kline, H. Gram, F. Di Padova, M. Zurini, J. Han, and R. J. Ulevitch. "Coordinate activation of endogenous p38a, β, γ, and δ by inflammatory stimuli." Journal of Leukocyte Biology 67, no. 5 (May 2000): 705–11. http://dx.doi.org/10.1002/jlb.67.5.705.
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Hu, Ping, Angel Nebreda, Helmut Hanenberg, Garrett Kinnebrew, Mircea Ivan, Mervin C. Yoder, Marie-Dominique Filippi, Hal E. Broxmeyer, and Reuben Kapur. "P38α/JNK Signaling Restrains Erythropoiesis By Suppressing Ezh2-Mediated Epigenetic Silencing of Bim." Blood 132, Supplement 1 (November 29, 2018): 3837. http://dx.doi.org/10.1182/blood-2018-99-117098.
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Abstract A remarkable feature of erythropoiesis is the coordination of proliferation, differentiation and apoptosis of erythroid cells to precisely achieve erythropoietic homeostasis to avoid anemia and polycythemia. Anemia is a common disease arising from various causes, including Myelodysplastic syndromes, thalassemia, cancer chemotherapy, chronic kidney disease and hemorrhage. The pro-erythropoietic factor erythropoietin (EPO) is often employed for anemia therapy. However, questions have been raised about the safety of EPO given its potential for tumor promotion in cancer-related anemia. Moreover, many acute and chronic anemias, including hemolysis, sepsis and genetic bone marrow failure diseases such as Diamond-Blackfan anemia are untreatable with EPO. To overcome these hurdles, new molecular mechanisms need to be identified that physiologically restrain erythropoiesis by acting as molecular brakes to prevent over-active erythropoiesis caused by pro-erythropoietic signals. Inhibiting these restraining mechanisms could provide alternative approaches to treat anemia in an EPO-independent fashion. P38 MAPK (Mitogen-activated protein kinase) is an important pathway involved in diverse biological processes. P38 modulates cell proliferation, controls cell survival and decides cell fate during differentiation. P38 pathway functions mainly by phosphorylating and activating important transcription factors in response to different stimuli, including ATF2, CREB, and MEF2. There are four members within the P38 MAPK family, including P38α, P38β, P38γ, and P38δ. These members are encoded by different genes and have different tissue expression patterns. Among them, P38α is ubiquitously expressed. P38α modulates the function of different cell types. There are two distinct developmental defects reported in global P38α knockout mice by two separate groups using different mouse strains. One displayed embryonic death with highly anemic appearance due to reduced EPO production and another showed even earlier embryonic lethality due to placental developmental defects. In a P38α conditional mice model in which Cre recombinase was expressed in the whole mouse embryo but not in the placenta by crossing to MORE-Cre mice, no anemia or EPO defects were observed. However, the intrinsic and cell autonomous role of P38α in adult steady-state or stressful erythropoiesis has not been established. Loss of P38α causes activation of JNK in the liver. P38 inhibitors are in clinical trials and have the potential for the treatment of human disease. Therefore, it is important to understand the down-stream targets and functional outcomes induced by P38α deficiency. Using primary human erythroblasts derived from human CD34+ hematopoietic stem and progenitor cells (HSPCs) and P38α conditional knockout mice, we find that P38α acts as a molecular brake during anemia recovery through integrating apoptotic signals and by shortening the lifespan of erythroblasts to prevent potential over-active erythropoiesis caused by pro-erythropoietic signaling. Loss of P38α in erythroblasts activates JNK through augmented Map3k4 via a negative feedback circuit revealed by gene expression profiling. Functionally, JNK serves as a pro-survival signal independent of EPO by compromising Bim expression via stabilizing the epigenetic silencer Ezh2 in erythroblasts. JNK-controlled Cdk1 activity modulates full interaction of Ezh2 to the E3 ligase Smurf2 through multiple threonine phosphorylation sites within Ezh2. Our findings identify a key signaling cascade involving P38α/JNK/Cdk1/smurf2/Ezh2/Bim in fine tuning stress erythropoiesis. We propose that inhibition of P38α may provide an alternative strategy for the treatment of anemia. Disclosures No relevant conflicts of interest to declare.
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Schonhoff, Christopher M., Se Won Park, Cynthia R. L. Webster, and M. Sawkat Anwer. "p38 MAPK α and β isoforms differentially regulate plasma membrane localization of MRP2." American Journal of Physiology-Gastrointestinal and Liver Physiology 310, no. 11 (June 1, 2016): G999—G1005. http://dx.doi.org/10.1152/ajpgi.00005.2016.
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In hepatocytes, cAMP both activates p38 mitogen-activated protein kinase (MAPK) and increases the amount of multidrug resistance-associated protein-2 (MRP2) in the plasma membrane (PM-MRP2). Paradoxically, taurolithocholate (TLC) activates p38 MAPK but decreases PM-MRP2 in hepatocytes. These opposing effects of cAMP and TLC could be mediated via different p38 MAPK isoforms (α and β) that are activated differentially by upstream kinases (MKK3, MKK4, and MKK6). Thus we tested the hypothesis that p38α MAPK and p38β MAPK mediate increases and decreases in PM-MRP2 by cAMP and TLC, respectively. Studies were conducted in hepatocytes isolated from C57BL/6 wild-type (WT) and MKK3-knockout (MKK3−/−) mice and in a hepatoma cell line (HuH7) that overexpresses sodium-taurocholate cotransporting polypeptide (NTCP) (HuH-NTCP). Cyclic AMP activated MKK3, p38 MAPK, and p38α MAPK and increased PM-MRP2 in WT hepatocytes, but failed to activate p38α MAPK or increase PM-MRP2 in MKK3−/− hepatocytes. In contrast to cAMP, TLC activated total p38 MAPK but decreased PM-MRP2, and did not activate MKK3 or p38α MAPK in WT hepatocytes. In MKK3−/− hepatocytes, TLC still decreased PM-MRP2 and activated p38 MAPK, indicating that these effects are not MKK3-dependent. Additionally, TLC activated MKK6 in MKK3−/− hepatocytes, and small interfering RNA knockdown of p38β MAPK abrogated TLC-mediated decreases in PM-MRP2 in HuH-NTCP cells. Taken together, these results suggest that p38α MAPK facilitates plasma membrane insertion of MRP2 by cAMP, whereas p38β MAPK mediates retrieval of PM-MRP2 by TLC.
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Jirmanova, Ludmila, Maria Letizia Giardino Torchia, Nandakumara D. Sarma, Paul R. Mittelstadt, and Jonathan D. Ashwell. "Lack of the T cell–specific alternative p38 activation pathway reduces autoimmunity and inflammation." Blood 118, no. 12 (September 22, 2011): 3280–89. http://dx.doi.org/10.1182/blood-2011-01-333039.
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Abstract Stimulation via the T-cell receptor (TCR) activates p38α and p38β by phosphorylation of p38 Tyr-323 (p38Y323). Here we characterize knockin mice in which p38α and/or β Tyr-323 has been replaced with Phe. We find that p38α accounts for two-thirds and p38β the remainder of TCR-induced p38 activation. T cells from double knockin mice (p38αβY323F) had defects in TCR-mediated proliferation and Th1 and Th17 skewing, the former corresponding with an inability to sustain T-bet expression. Introduction of p38αY323F into Gadd45α-deficient mice, in which the alternative p38 pathway is constitutively active, reversed T-cell hyperproliferation and autoimmunity. Furthermore, p38αβY323F mice had delayed onset and reduced severity of the inflammatory autoimmune diseases collagen-induced arthritis and experimental autoimmune encephalomyelitis. Thus, T cell-specific alternative activation of p38 is an important pathway in T-cell proliferation, Th skewing, and inflammatory autoimmunity, and may be an attractive tissue-specific target for intervention in these processes.
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Scheijen, Blanca, Hai T. Ngo, and James D. Griffin. "FOXO Transcription Factors Are Negatively Regulated by p38 Map Kinases Downstream of FLT3 Receptor Signaling." Blood 106, no. 11 (November 16, 2005): 203. http://dx.doi.org/10.1182/blood.v106.11.203.203.
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Abstract The phosphoinositide 3-kinase (PI3K)-AKT/PKB signal transduction cascade is an evolutionarily conserved pathway regulating the FOXO subclass of Forkhead transcription factors (FOXO1, FOXO3a and FOXO4) downstream of insulin, cytokine and growth factor receptors. When PI3K phospholipid kinase activity is low, FOXO proteins localize to the nucleus where they induce expression of genes that promote programmed cell death (FasL, Bim, TRAIL), inhibit cell cycle progression (p27KIP1, Rb related family member p130), facilitate DNA repair (GADD45) and protect against oxidative damage (MnSOD). Following receptor stimulation, increased levels of PtdIns(3,4,5)P3 are generated at the plasma membrane resulting in PDK1-mediated activation of the serine/threonine kinase AKT/PKB. Subsequent phosphorylation of FOXO proteins by AKT/PKB results in their active sequestration in the cytoplasm through binding to 14-3-3 proteins, thereby blocking their action as transcription factors. Recently, it has become evident that FOXO proteins can also be regulated through other signaling pathways. One example is phosphorylation and activation of FOXO4 by stress kinases JNK/SAPK in response to oxidative stress (Essers et al., 2004; EMBO J. 23:4802–12). Here, we report that p38 mitogen activated protein kinases (MAPK) negatively regulate FOXO transcription factors downstream of FLT3 receptor tyrosine kinase signaling. Stimulation of human wild-type FLT3 receptor with FLT3 ligand, or expression of constitutively active mutants FLT3-ITD or FLT3-D835Y in Ba/F3 cells resulted in activation of p38 MAPK and phosphorylation of its known substrate ATF2 on threonine residue 71 (Thr71). Transient luciferase reporter assays showed that expression of a constitutively active MKK3 or MKK6, upstream activators of p38 MAPK, inhibited FOXO-induced gene transcription. The p38 MAPK inhibitors SB202190 and SB203580 as well as dominant-negative p38 MAPK blocked FLT3-mediated inhibition of FOXO transcription activation, suggesting p38 MAPK is both necessary and sufficient for FOXO regulation. In vitro kinase assays demonstrated that FOXO proteins are directly phosphorylated by p38 MAPK, although different p38 MAPK family members (p38α, p38β 2, p38γ and p38δ) displayed distinct FOXO protein substrate specificity. In conclusion, our data demonstrate that FOXO proteins are novel substrates of p38 MAP kinases and activation of p38 MAPK through FLT3 receptor signaling represents an important pathway to attenuate FOXO target gene regulation.
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Wijayanti, Nastiti, Thomas Kietzmann, and Stephan Immenschuh. "Heme Oxygenase-1 Gene Activation by the NAD(P)H Oxidase Inhibitor 4-(2-Aminoethyl) Benzenesulfonyl Fluoride via a Protein Kinase B, p38-dependent Signaling Pathway in Monocytes." Journal of Biological Chemistry 280, no. 23 (April 15, 2005): 21820–29. http://dx.doi.org/10.1074/jbc.m502943200.
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Heme oxygenase (HO)-1 is the inducible isoform of the rate-limiting enzyme of heme degradation and modulates the inflammatory immune response. Because HO-1 is up-regulated by NAD(P)H oxidase activators such as lipopolysaccharide and 12-O-tetradecanoylphorbol-13-acetate in monocytic cells, we investigated the gene regulation of HO-1 by the chemical NAD(P)H oxidase inhibitor 4-(2-aminoethyl) benzenesulfonyl fluoride (AEBSF). Unexpectedly, AEBSF induced endogenous gene expression and promoter activity of HO-1 in cell cultures of human and mouse monocytes. Inhibition of the phosphatidylinositol 3-kinase/protein kinase B (PKB) pathway by pharmacological inhibitors and cotransfection of an expression vector for a dominant negative mutant of PKB reduced the AEBSF-dependent induction of HO-1 gene transcription. Accordingly, overexpressed constitutively active PKB markedly up-regulated HO-1 promoter activity. AEBSF activated the mitogen-activated protein kinases (MAPK) JNK and p38. Inhibition of p38α and p38β, but not that of JNK or p38γ and p38δ, prevented the induction of HO-1 gene expression by AEBSF. p38 was stimulated by AEBSF in a PKB-dependent manner as demonstrated by a luciferase assay with a Gal4-CHOP fusion protein. Finally, AEBSF- and PKB-dependent induction of HO-1 promoter activity was reduced by simultaneous mutation of an E-box motif (–47/–42) and a cAMP response element/AP-1 element (–664/–657) of the proximal HO-1 gene promoter. Overexpression of the basic helix-loop-helix transcription factor USF2 and coactivator p300 enhanced the AEBSF-dependent response of the HO-1 promoter. The data suggest that the transcriptional induction of HO-1 gene expression by AEBSF is mediated via activation of a PKB, p38 MAPK signaling pathway.
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Wu, Lihua, Ping Xiao, Qi Li, Zhen Zhang, Hui Wang, Qian Jiang, and Long Li. "Altered expression of AKT1 and P38A in the colons of patients with Hirschsprung’s disease." Pediatric Surgery International 36, no. 6 (March 31, 2020): 719–25. http://dx.doi.org/10.1007/s00383-020-04653-9.
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Lui, Paul, Chenbo Zeng, Stephen Acton, Steven Cok, Alison Sexton, and Aubrey R. Morrison. "Effects of p38MAPK isoforms on renal mesangial cell inducible nitric oxide synthase expression." American Journal of Physiology-Cell Physiology 286, no. 1 (January 2004): C145—C152. http://dx.doi.org/10.1152/ajpcell.00233.2003.
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Several related isoforms of p38MAPK have been identified and cloned in many species. Although they all contain the dual phosphorylation motif TGY, the expression of these isoforms is not ubiquitous. p38α and -β2 are ubiquitously expressed, whereas p38γ and -δ appear to have more restricted expression. Because there is evidence for selective activation by upstream kinases and selective preference for downstream substrates, the functions of these conserved proteins is still incompletely understood. We have demonstrated that the renal mesangial cell expresses the mRNA for all the isoforms of p38MAPK, with p38α mRNA expressed at the highest level, followed by p38γ and the lowest levels of expression by p38β2 and -δ. To determine the functional effects of these proteins on interleukin (IL)-1β-induced inducible nitric oxide synthase (iNOS) expression, we transduced TAT-p38 chimeric proteins into renal mesangial cells and assessed the effects of wild-type and mutant p38 isoforms on ligand induced iNOS expression. We show that whereas p38γ and -δ had minimal effects on iNOS expression, p38α and -β2 significantly altered its expression. p38α mutant and p38β2 wild-type dose dependently inhibited IL-1β-induced iNOS expression. These data suggest that p38α and β2 have reciprocal effects on iNOS expression in the mesangial cell, and these observations may have important consequences for the development of selective inhibitors targeting the p38MAPK family of proteins.
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Qin, W., Z. M. Lin, R. Deng, D. D. Li, Z. Song, Y. G. Tian, R. F. Wang, J. Q. Ling, and X. F. Zhu. "p38a MAPK is involved in BMP-2-induced odontoblastic differentiation of human dental pulp cells." International Endodontic Journal 45, no. 3 (October 12, 2011): 224–33. http://dx.doi.org/10.1111/j.1365-2591.2011.01965.x.
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Hsu, Ren-Jun, Chiu-Chun Lin, Ying-Fang Su, and Huai-Jen Tsai. "dickkopf-3-related Gene Regulates the Expression of Zebrafishmyf5Gene through Phosphorylated p38a-dependent Smad4 Activity." Journal of Biological Chemistry 286, no. 8 (December 15, 2010): 6855–64. http://dx.doi.org/10.1074/jbc.m110.161638.
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Tong, S. "SCIO-469, a novel P38A MAPK Inhibitor, provides efficacy in acute post-surgical dental pain." Clinical Pharmacology & Therapeutics 75, no. 2 (February 2004): P3. http://dx.doi.org/10.1016/j.clpt.2003.11.011.
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Ren, Shuxun, Gang Lu, Jeffery B. Badwed, Huiping Jiang, and Yibin Wang. "The In Vivo Role of p38a in Pressure-Overload Induced Hypertrophy and Ischemia/Reperfusion Injury." Journal of Cardiac Failure 12, no. 6 (August 2006): S15. http://dx.doi.org/10.1016/j.cardfail.2006.06.056.
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Gattenloehner, Stefan, Sergei Chuvpilo, Claudia Langebrake, Dirk Reinhardt, Hans-Konrad Müller-Hermelink, Edgar Serfling, Angela Vincent, and Alexander Marx. "Novel RUNX1 isoforms determine the fate of acute myeloid leukemia cells by controlling CD56 expression." Blood 110, no. 6 (September 15, 2007): 2027–33. http://dx.doi.org/10.1182/blood-2007-02-074203.
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Abstract CD56high acute myeloid leukemias (AMLs) have a poor prognosis, but it has been unclear how CD56 expression is controlled and how it relates to clinical aggressiveness. We show that CD56 expression on AML cells correlates with an abnormal expression pattern of runt-related transcription factor 1 (RUNX1) isoforms. Whereas full-length p48 RUNX1 (p48) up-regulated CD56 in AML cells, 3 previously unknown shorter RUNX1 isoforms, p38a, p30, and p24, suppressed CD56 expression. Both p48 and CD56 induced nuclear translocation of nuclear factor (NF)–κB and increased bcl2L12 expression, and inhibition of this pathway by small inhibitory RNA-mediated p48 knock down or NF-κB blockade substantially increased apoptosis in CD56+ AML cell lines. These findings indicate the potential for new therapy of CD56high AML by suppression of the “overactive” RUNX1/CD56/NF-κB signaling pathway(s).
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Antonescu, C. N., C. Huang, W. Niu, Z. Liu, P. A. Eyers, K. A. Heidenreich, P. J. Bilan, and A. Klip. "Reduction of Insulin-Stimulated Glucose Uptake in L6 Myotubes by the Protein Kinase Inhibitor SB203580 Is Independent of p38MAPK Activity." Endocrinology 146, no. 9 (September 1, 2005): 3773–81. http://dx.doi.org/10.1210/en.2005-0404.
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Abstract Insulin increases glucose uptake through translocation of the glucose transporter GLUT4 to the plasma membrane. We previously showed that insulin activates p38MAPK, and inhibitors of p38MAPKα and p38MAPKβ (e.g. SB203580) reduce insulin-stimulated glucose uptake without affecting GLUT4 translocation. This observation suggested that insulin may increase GLUT4 activity via p38α and/or p38β. Here we further explore the possible participation of p38MAPK through a combination of molecular strategies. SB203580 reduced insulin stimulation of glucose uptake in L6 myotubes overexpressing an SB203580-resistant p38α (drug-resistant p38α) but barely affected phosphorylation of the p38 substrate MAPK-activated protein kinase-2. Expression of dominant-negative p38α or p38β reduced p38MAPK phosphorylation by 70% but had no effect on insulin-stimulated glucose uptake. Gene silencing via isoform-specific small interfering RNAs reduced expression of p38α or p38β by 60–70% without diminishing insulin-stimulated glucose uptake. SB203580 reduced photoaffinity labeling of GLUT4 by bio-LC-ATB-BMPA only in the insulin-stimulated state. Unless low levels of p38MAPK suffice to regulate glucose uptake, these results suggest that the inhibition of insulin-stimulated glucose transport by SB203580 is likely not mediated by p38MAPK. Instead, changes experienced by insulin-stimulated GLUT4 make it susceptible to inhibition by SB203580.
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Abdelfadil, Ehab, Ya-Hsin Cheng, Da-Tian Bau, Wei-Jen Ting, Li-Mien Chen, Hsi-Hsien Hsu, Yueh-Min Lin, et al. "Thymoquinone Induces Apoptosis in Oral Cancer Cells Through P38β Inhibition." American Journal of Chinese Medicine 41, no. 03 (January 2013): 683–96. http://dx.doi.org/10.1142/s0192415x1350047x.
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Oral cancer is a common malignancy associated with high morbidity and mortality. While p38 MAPK is reported to be involved in different cellular activities such as proliferation and differentiation, reports rarely define the roles of the individual members of the p38 MAPK family in cancer. We used two unique cell lines developed by our lab representing chemically induced oral cancer cells (T28) and non-tumor cells (N28) obtained from tissues surrounding the induced cancer as a model to screen out whether p38 MAPK is involved in the malignant transformation processes. The results suggest an association between p38β not p38α and oral cancer development. Additionally, the anti-cancer activity of thymoquinone (TQ) was screened out and we found evidences suggesting that the anti-tumor activity of TQ may be attributed to the downregulation of p38β MAPK.
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Ohnishi, Eriko, Toshiyasu Goto, Atsushi Sato, Mi-sun Kim, Shun-ichiro Iemura, Tohru Ishitani, Tohru Natsume, Junji Ohnishi, and Hiroshi Shibuya. "Nemo-Like Kinase, an Essential Effector of Anterior Formation, Functions Downstream of p38 Mitogen-Activated Protein Kinase." Molecular and Cellular Biology 30, no. 3 (November 23, 2009): 675–83. http://dx.doi.org/10.1128/mcb.00576-09.
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ABSTRACT Nemo-like kinase (NLK) is known to function as a mitogen-activated protein kinase (MAPK)-like kinase. However, the upstream molecules and molecular mechanisms that regulate NLK activity remain unclear. In the present study, we identified p38 MAPK as an upstream kinase and activator of NLK. p38 regulates the function of NLK via phosphorylation, and this modification can be abrogated by depletion of endogenous p38. In Xenopus laevis embryos, depletion of either p38β or NLK by antisense morpholino oligonucleotides results in a severe defect in anterior development and impaired expression of endogenous anterior markers. It is notable that morphants of Xenopus p38α, another isoform of the p38 MAPK family, exhibited no obvious defects in anterior development. Defects in head formation or in the expression of anterior marker genes caused by suppression of endogenous p38β expression could be rescued by expression of wild-type NLK but not by expression of mutant NLK lacking the p38β phosphorylation site. In contrast, defects in head formation or in the expression of anterior marker genes caused by suppression of endogenous NLK expression could not be rescued by expression of p38. These results provide the first evidence that p38 specifically regulates NLK function, which is required for anterior formation in Xenopus development.
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Schnöder, Laura. "P1-135: Deficiency of Neuronal P38A-Mapk Attenuates Amyloid Pathology and Cognitive Deficits in Alzheimer’S Mouse Model." Alzheimer's & Dementia 12 (July 2016): P455. http://dx.doi.org/10.1016/j.jalz.2016.06.884.
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Sahu, Vishal, Lokesh Nigam, Vertica Agnihotri, Abhishek Gupta, Shashank Shekhar, Naidu Subbarao, Suman Bhaskar, and Sharmistha Dey. "Diagnostic Significance of p38 Isoforms (p38α, p38β, p38γ, p38δ) in Head and Neck Squamous Cell Carcinoma: Comparative Serum Level Evaluation and Design of Novel Peptide Inhibitor Targeting the Same." Cancer Research and Treatment 51, no. 1 (January 15, 2019): 313–25. http://dx.doi.org/10.4143/crt.2018.105.
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Nguyen, Aaron N., Mamatha Reddy, Margaret Henson, Elizabeth G. Stebbins, Gilbert O’Young, Jing Y. Ma, Edwin Haghnazari, et al. "SCIO-469, a Potent and Selective Inhibitor of p38a MAPK, Normalizes the Bone Marrow Microenvironment and Inhibits Multiple Myeloma Cell Proliferation in In Vitro and In Vivo Models." Blood 104, no. 11 (November 16, 2004): 1501. http://dx.doi.org/10.1182/blood.v104.11.1501.1501.
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Abstract Despite recent advances in the treatment of multiple myeloma (MM), this disease remains incurable. Accumulating evidence suggest that the bone marrow (BM) microenvironment of MM plays a critical role in tumor growth, survival, and drug resistance. A key aspect of this tumor-supportive environment is elevated levels of cytokines and other soluble factors. Most prominent among these is IL-6, which acts as a survival factor for MM cells and promotes their proliferation, migration, and drug resistance. Other mediators also implicated in the disease are VEGF and TNFa. The p38 MAPK is activated by a multitude of signals, including pro-inflammatory cytokines (e.g., TNFa and IL-1ß) and environmental stress. Furthermore, p38 activation has been shown to be important for the synthesis and secretion of IL-6, VEGF, and TNFa. Consequently, inhibition of p38 is postulated to reduce the production of these factors implicated in MM and to have therapeutic benefit by suppressing the tumor-supportive state of the BM microenvironment. Here, we demonstrate that SCIO-469, a specific and potent inhibitor of p38a MAPK, strongly inhibits MM cell proliferation by affecting MM cells directly as well as the BM microenvironment. SCIO-469 directly inhibits MM cell proliferation in long term culture. Importantly, SCIO-469 potently inhibits IL-6 and VEGF secretion from BM stromal cells (BMSC). To examine the effect of inhibiting BMSC-derived factors important in MM, we measured MM cell proliferation using transwell plates that separate BMSC from MM cells via a porous membrane. In transwell plates containing only MM cells, MM cell proliferation was modest and was inhibited by SCIO-469. In contrast, the presence of BMSC in transwell inserts dramatically increased the proliferation of MM cells over the course of the study. This result suggests that factors (e.g., IL-6) secreted by BMSC greatly stimulate MM cell proliferation. When SCIO-469 was added to these transwell cultures containing BMSC, MM cell proliferation was inhibited significantly. Consistent with these results, we show that levels of IL-6 under these conditions mirror exactly the proliferation of MM cells; IL-6 level is high in vehicle-treated cultures and is suppressed in SCIO-469-treated cultures. Finally, in a mouse xenograft plasmacytoma model of MM, we show that p38 inhibition significantly inhibited the increase in MM tumor volume. Collectively, our data indicate that SCIO-469 is a suppressor of the BM microenvironment and an effective inhibitor of MM cell proliferation in vitro and in vivo. Since SCIO-469 also inhibits secretion of osteoclast-stimulating factors (RANKL, IL-11, and MIP1a) in the microenvironment, SCIO-469 may not only inhibit MM cell survival but may also alleviate bone-related pathologies (bone destruction and osteolytic lesions) commonly associated with MM. Therefore, SCIO-469 may offer great promise for an improved outcome for patients with MM.
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Alam, Muhammad S., Matthias M. Gaida, Youichi Ogawa, Antonios G. A. Kolios, Felix Lasitschka, and Jonathan D. Ashwell. "Counter-regulation of T cell effector function by differentially activated p38." Journal of Experimental Medicine 211, no. 6 (May 26, 2014): 1257–70. http://dx.doi.org/10.1084/jem.20131917.
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Unlike the MAP kinase (MAPK) cascade that phosphorylates p38 on the activation loop, T cell receptor (TCR) signaling results in phosphorylation on Tyr-323 (pY323, alternative pathway). Using mice expressing p38α and p38β with Y323F substitutions, we show that alternatively but not MAPK cascade-activated p38 up-regulates the transcription factors NFATc1 and IRF4, which are required for proliferation and cytokine production. Conversely, activation of p38 with UV or osmotic shock mitigated TCR-mediated activation by phosphorylation and cytoplasmic retention of NFATc1. Notably, UVB treatment of human psoriatic lesions reduced skin-infiltrating p38 pY323+ T cell IRF4 and IL-17 production. Thus, distinct mechanisms of p38 activation converge on NFATc1 with opposing effects on T cell immunity, which may underlie the beneficial effect of phototherapy on psoriasis.
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Lim, Seunghwan, Yonglong Zou, and Eileen Friedman. "The Transcriptional Activator Mirk/Dyrk1B Is Sequestered by p38α/β MAP Kinase." Journal of Biological Chemistry 277, no. 51 (October 15, 2002): 49438–45. http://dx.doi.org/10.1074/jbc.m206840200.
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Mirk/Dyrk1B protein kinase was shown in an earlier study to function as a transcriptional activator of HNF1α, which Mirk phosphorylates at Ser249within its CREB (cAMP-response element-binding protein)-binding protein (CBP) binding domain (1). The MAPK kinase MKK3 was also shown to activate Mirk as a protein kinase, implicating Mirk in the biological response to certain stress agents. Another MKK3 substrate, p38MAPK, is now shown to inhibit the function of Mirk as a transcriptional activator in a kinase-independent manner. Co-immunoprecipitation experiments demonstrated that kinase-inactive p38AF, as well as wild-type p38, sequestered Mirk and prevented its association with MKK3. Only the p38α and p38β isoforms, but not the γ or δ isoforms, complexed with Mirk. p38αMAPK blocked Mirk activation of HNF1α in a dose-dependent manner, with high levels of kinase-inactive p38αAF completely suppressing the activity of Mirk. Size fractionation by fast protein liquid chromatography on Superdex 200 demonstrated that Mirk is not found as a monomerin vivo, but is found within 150–700 kDa subnuclear complexes, which co-migrate with the nuclear body scaffolding protein PML. Endogenous Mirk, p38, and MKK3 co-migrate within 500–700-kDa protein complexes, which accumulate when nuclear export is blocked by leptomycin B. Stable overexpression of Mirk increases the fraction of Mirk protein and p38 protein within these 500–700 kDa complexes, suggesting that the complexes act as nuclear depots for Mirk and p38. Sequestration of Mirk by p38 may occur within these subnuclear complexes. Synchronization experiments demonstrated that Mirk levels fluctuate about 10-fold within the cell cycle, while p38 levels do not, leading to the speculation that endogenous p38 could only block Mirk function when Mirk levels were low in S phase and not when Mirk levels were elevated in G0/G1. These data suggest a novel cell cycle-dependent function for p38, suppression of the function of Mirk as a transcriptional activator only when cells are proliferating, and thus limiting Mirk function to growth-arrested cells.
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Wang, Qin, Michael Yerukhimovich, William A. Gaarde, Ian J. Popoff, and Claire M. Doerschuk. "MKK3 and -6-dependent activation of p38α MAP kinase is required for cytoskeletal changes in pulmonary microvascular endothelial cells induced by ICAM-1 ligation." American Journal of Physiology-Lung Cellular and Molecular Physiology 288, no. 2 (February 2005): L359—L369. http://dx.doi.org/10.1152/ajplung.00292.2004.
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Previous studies demonstrated that neutrophil adherence induces ICAM-1-dependent cytoskeletal changes in TNF-α-treated pulmonary microvascular endothelial cells that are prevented by a pharmacological inhibitor of p38 MAP kinase. This study determined whether neutrophil adherence induces activation of p38 MAP kinase in endothelial cells, the subcellular localization of phosphorylated p38, which MAP kinase kinases lead to p38 activation, which p38 isoform is activated, and what the downstream targets may be. Confocal microscopy showed that neutrophil adhesion for 2 or 6 min induced an increase in phosphorylated p38 in endothelial cells that was punctate and concentrated in the central region of the endothelial cells. Studies using small interfering RNA (siRNA) to inhibit the protein expression of MAP kinase kinase 3 and 6, either singly or in combination, showed that both MAP kinase kinases were required for p38 phosphorylation. Studies using an antisense oligonucleotide to p38α demonstrated that inhibition of the protein expression of p38α 1) inhibited activation of p38 MAP kinase without affecting the protein expression of p38β; 2) prevented phosphorylation of heat shock protein 27, an actin binding protein that may induce actin polymerization upon phosphorylation; 3) attenuated cytoskeletal changes; and 4) attenuated neutrophil migration to the EC borders. Thus MAP kinase kinase3- and 6-dependent activation of the α-isoform of p38 MAP kinase is required for the cytoskeletal changes induced by neutrophil adherence and influences subsequent neutrophil migration toward endothelial cell junctions.
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McNEILL, Helen, Axel KNEBEL, J. Simon C. ARTHUR, Ana CUENDA, and Philip COHEN. "A novel UBA and UBX domain protein that binds polyubiquitin and VCP and is a substrate for SAPKs." Biochemical Journal 384, no. 2 (November 23, 2004): 391–400. http://dx.doi.org/10.1042/bj20041498.
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A widely expressed protein containing UBA (ubiquitin-associated) and UBX (ubiquitin-like) domains was identified as a substrate of SAPKs (stress-activated protein kinases). Termed SAKS1 (SAPK substrate-1), it was phosphorylated efficiently at Ser200in vitro by SAPK3/p38γ, SAPK4/p38δ and JNK (c-Jun N-terminal kinase), but weakly by SAPK2a/p38α, SAPK2b/p38β2 or ERK (extracellular-signal-regulated kinase) 2. Ser200, situated immediately N-terminal to the UBX domain, became phosphorylated in HEK-293 (human embryonic kidney) cells in response to stressors. Phosphorylation was not prevented by SB 203580 (an inhibitor of SAPK2a/p38α and SAPK2b/p38β2) and/or PD 184352 (which inhibits the activation of ERK1 and ERK2), and was similar in fibroblasts lacking both SAPK3/p38γ and SAPK4/p38δ or JNK1 and JNK2. SAKS1 bound ubiquitin tetramers and VCP (valosin-containing protein) in vitro via the UBA and UBX domains respectively. The amount of VCP in cell extracts that bound to immobilized GST (glutathione S-transferase)–SAKS1 was enhanced by elevating the level of polyubiquitinated proteins, while SAKS1 and VCP in extracts were coimmunoprecipitated with an antibody raised against S5a, a component of the 19 S proteasomal subunit that binds polyubiquitinated proteins. PNGase (peptide N-glycanase) formed a 1:1 complex with VCP and, for this reason, also bound to immobilized GST–SAKS1. We suggest that SAKS1 may be an adaptor that directs VCP to polyubiquitinated proteins, and PNGase to misfolded glycoproteins, facilitating their destruction by the proteasome.
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Romero-Becerra, Rafael, Ayelén Santamans, Cintia Folgueira, and Guadalupe Sabio. "p38 MAPK Pathway in the Heart: New Insights in Health and Disease." International Journal of Molecular Sciences 21, no. 19 (October 8, 2020): 7412. http://dx.doi.org/10.3390/ijms21197412.
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The p38 mitogen-activated kinase (MAPK) family controls cell adaptation to stress stimuli. p38 function has been studied in depth in relation to cardiac development and function. The first isoform demonstrated to play an important role in cardiac development was p38α; however, all p38 family members are now known to collaborate in different aspects of cardiomyocyte differentiation and growth. p38 family members have been proposed to have protective and deleterious actions in the stressed myocardium, with the outcome of their action in part dependent on the model system under study and the identity of the activated p38 family member. Most studies to date have been performed with inhibitors that are not isoform-specific, and, consequently, knowledge remains very limited about how the different p38s control cardiac physiology and respond to cardiac stress. In this review, we summarize the current understanding of the role of the p38 pathway in cardiac physiology and discuss recent advances in the field.
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Vellón, L., L. Espinosa Hevia, F. Royo, and L. A. Parada. "α5β1 integrin-emanating signals remodel nuclear architecture through the activation of ERK1/2 and p38a MAPKs during invasive cell growth." European Journal of Cancer Supplements 6, no. 9 (July 2008): 36. http://dx.doi.org/10.1016/s1359-6349(08)71313-2.
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XU, Jiahua, Richard A. CLARK, and William C. PARKS. "p38 mitogen-activated kinase is a bidirectional regulator of human fibroblast collagenase-1 induction by three-dimensional collagen lattices." Biochemical Journal 355, no. 2 (April 6, 2001): 437–47. http://dx.doi.org/10.1042/bj3550437.
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When fibroblasts are cultured in contracting collagen matrices, matrix metalloproteinase-1 (MMP-1, collagenase-1) is induced. In the present study we demonstrate that p38α mitogen-activated protein kinase (p38α MAPK) plays a bi-directional role in the MMP-1 response to contracting floating collagen lattices (fl-coll). fl-coll, but not attached collagen lattices (att-coll), co-ordinately increased expression of MMP-1 and activities of p38α and MKK3/6 (MAPK kinase 3/6). However, treatment of primary fibroblasts cultured in fl-coll with increasing doses of SB203580, an inhibitor of p38α and p38β, caused a bipolar pattern of MMP-1 expression. Partial inhibition of p38 MAPK activity resulted in the lowest level of MMP-1 expression, whereas total inhibition of p38 activity led to MMP-1 levels as high as in the absence of inhibitor. The activation/inhibition of p38α was apparently responsible for the observed phenomena, as supported by three lines of evidence. (1) p38α was the predominant isoform sensitive to SB203580 in primary fibroblasts. (2) Fibroblasts transfected with increasing dose of a dominant negative p38α (p38DN) similarly demonstrated the bipolar pattern of MMP-1 expression induced by fl-coll. (3) The bipolar MMP-1 expression occurred during the gradual, linear inhibition of p38α kinase activity by both inhibitors, SB203580 and p38DN. Nuclear factor-κB (NF-κB), a previously identified positive regulator of MMP-1 expression induced by fl-coll [Xu, Zutter, Santoro and Clark (1998) J. Cell Biol. 140, 709-719] was mediated by fl-coll-activated p38α. However, the fl-coll-induced expression of MMP-1 facilitated by p38α suppression was maintained independent of NF-κB activity, suggesting the existence of a p38α-dependent antagonistic pathway. We conclude that fl-coll-induced MMP-1 expression is the net outcome of opposing effects mediated by p38α. Therefore, the level of p38α kinase activity may provide a fine-tuned control of MMP-1 gene expression in response to biomechanical signals.
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Carlsson, Stina, and J. Gierow. "p38 Mitogen-activated protein kinase modulates exocrine secretion in rabbit lacrimal gland." Cellular and Molecular Biology Letters 17, no. 1 (January 1, 2012): 1–10. http://dx.doi.org/10.2478/s11658-011-0031-y.
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AbstractThe lacrimal gland (LG) is an exocrine gland important for secretion of the tear film. The kinase p38 has important signal transduction functions, e.g. in gene transcription, but has previously not been known to modulate exocrine secretion. The aim of the current study was to investigate the role of p38 in carbachol (Cch)-induced LG secretion in LG acinar cells in vitro. Western blotting was used to determine the phosphorylation status of p38 and p42/44 and determine expression of p38 isoforms. To determine the effect of p38 inhibition on LG secretion, PD 169316, a general p38 inhibitor, and SB 239063, an inhibitor of p38α and β, were added to the cells prior to secretion measurements. The results revealed activation of p38 mediated by Cch stimulation and inhibition of Cch-induced secretion as a result of p38 inhibition. The inhibition was observed with PD 169316 isoforms, but not with SB 239063. The p38δ isoform was shown to have robust expression both by Western blotting of acinar cells and immunofluorescence of the whole gland. In conclusion, p38 activation mediates secretion in cholinergic stimulation of rabbit LG cells.
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Schoorlemmer, Jon, and Mitchell Goldfarb. "Fibroblast Growth Factor Homologous Factors and the Islet Brain-2 Scaffold Protein Regulate Activation of a Stress-activated Protein Kinase." Journal of Biological Chemistry 277, no. 51 (September 18, 2002): 49111–19. http://dx.doi.org/10.1074/jbc.m205520200.
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Fibroblast growth factor homologous factors (FHFs) form native intracellular complexes with the mitogen-activated protein kinase (MAPK) scaffold protein islet-brain 2 (IB2) in adult brain. FHF binding to IB2 facilitates recruitment of the MAPK p38δ (SAPK4), while failing to stimulate binding of JNK, the preferred kinase of the related scaffold IB1 (JIP-1). We now report further biochemical evidence supporting FHFs as regulators of IB2 scaffold activity. Mixed lineage kinase 3 (MLK3) and IB2 synergistically activate p38δ but not the MAPKs JNK-1 and p38α. Binding of p38δ to IB2 is mediated by the carboxyl-terminal half of the scaffold (IB2Δ1–436). FHF2 also binds weakly to IB2Δ1–436and can thereby increase p38δ interaction with IB2Δ1–436. FHF-induced recruitment of p38δ to IB2 is accompanied by increased levels of activated p38δ, and synergistic activation of p38δ by MLK3 and IB2 is further enhanced by FHF2. Consistent with a role for FHFs as signaling molecules, FHF2 isolated from rat brain is serine/threonine-phosphorylated, and FHF can serve as a substrate for p38δin vitro. These results support the existence of a signaling module in which IB2 scaffolds a MLK3/MKK/p38δ kinase cascade. FHFs aid in recruitment of p38 to IB2 and may serve as kinase substrates.
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DESBIENS, Katia M., Réna G. DESCHESNES, Mireille M. LABRIE, Yan DESFOSSÉS, Herman LAMBERT, Jacques LANDRY, and Kerstin BELLMANN. "c-Myc potentiates the mitochondrial pathway of apoptosis by acting upstream of apoptosis signal-regulating kinase 1 (Ask1) in the p38 signalling cascade." Biochemical Journal 372, no. 2 (June 1, 2003): 631–41. http://dx.doi.org/10.1042/bj20021565.
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Cell transformation by growth-promoting oncoproteins renders cells extremely sensitive to apoptosis through an unknown mechanism affecting the mitochondrial pathway of apoptosis. We have shown previously that sensitization to apoptosis also correlated with the activation of the stress-activated protein kinase p38. In the present study, we investigated the role of p38 in c-Myc-dependent apoptosis induced by the anticancer agent cisplatin. Cisplatin treatment of Rat1 cells with deregulated expression of c-Myc resulted in nuclear fragmentation that was accompanied in all cells by the activation of Bax and the translocation of cytochrome c from the mitochondria to the cytoplasm. None of these features of apoptosis was induced in control Rat-1 cells. p38 was also activated by cisplatin only in cells with deregulated expression of c-Myc, but, in contrast with all features of apoptosis, this activation was not affected by Bcl-2. Remarkably, overexpression of an interfering mutant of the p38α isoform, but not p38β, blocked cisplatin-induced Bax activation or cytochrome c release and nuclear fragmentation. Analysis of the kinase cascade upstream of p38 revealed a c-Myc-dependent activation by cisplatin of mitogen-activated protein kinase kinase (MKK) 3/6 and apoptosis signal-regulating kinase 1 (Ask1). Inhibition of Ask1 blocked p38 activation by cisplatin and all features of apoptosis. Several of these data were confirmed using other DNA-damaging agents. The findings indicated that c-Myc potentiation of the mitochondrial pathway of apoptosis results, at least in part, from a sensitization of Ask1 activation, allowing DNA-damaging agents to induce in cascade Ask1, p38α and Bax.
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Ruiz-Bonilla, Vanessa, Eusebio Perdiguero, Lionel Gresh, Antonio L. Serrano, Mònica Zamora, Pedro Sousa-Victor, Mercè Jardí, Erwin F. Wagner, and Pura Muñoz-Cánoves. "Efficient adult skeletal muscle regeneration in mice deficient in p38β, p38γ and p38δ MAP kinases." Cell Cycle 7, no. 14 (July 15, 2008): 2208–14. http://dx.doi.org/10.4161/cc.7.14.6273.
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Siegel, David S., A. Krishnan, S. Lonial, G. Chatta, M. Alsina, S. Jagannath, P. Richardson, et al. "Phase II Trial of SCIO-469 as Monotherapy (M) or in Combination with Bortezomib (MB) in Relapsed Refractory Multiple Myeloma (MM)." Blood 108, no. 11 (November 16, 2006): 3580. http://dx.doi.org/10.1182/blood.v108.11.3580.3580.
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Abstract Background: p38a mitogen-activated protein kinase (MAPK) mediates production of proinflammatory cytokines and other factors including PGE-2 induced RANKL and IL-1 induced IL-6. SCIO-469 inhibits p38a MAPK blocking synthesis of Il-1ß, PGE2, VEGF, MIP-1α and TNFα thus reducing in vitro MM tumor growth and survival, and drug resistance. Objectives: Assess efficacy, safety, tolerability of SCIO-469 as M or MB in patients (pts) with relapsed and refractory multiple myeloma. Methods: Pts were treated with SCIO-469 alone (60 mg po tid)and assessed on Days 15, 30, 52 and 73. Bortezomib (1.0–1.3mg/m2 d 1,4,8,11 q21d) was added to M for PD or SD. Pts who had clinical benefit on either M or MB at Day 73 were allowed to continue on extension study for up to a total of 168 d, to further evaluate efficacy and saftey of M or MB. Results: 62 pts were enrolled: 39 M, 23 F, median age was 63 years (range 48–84), D-S stage at Dx: I (6%), II (32), III (60%%); median time from diagnosis to treatment 3.1 years; median # prior Rx = 5; including 29% with > 6; 71% prior transplant. 27 had received prior bortezomib and 17 were considered refractory. All 62 pts received study drug; 34 pts received MB at some time during the treatment period. 5 of the 28 (18%) pts treated with M and 25 of 34 (74%) pts treated with MB continued on the extension study. Median time on study was 77.5 d (range 7–304) for M and 180.5 d (range 34–275) for MB. Best response (EBMT; Blade 1998) to M was stable disease in 24% of pts; the best response to MB was 9/34 PR (26%), 2/34 MR (6%),3/34 SD (9%). Median time to progression (TTP) was 50 days for M compared to 140 days for MB. Safety/Tolerability: Adverse events on M were tabulated separately from those on MB. Neutropenia was minimal, < 3% with either regimen; anemia (47 vs 29%) and thrombocytopenia (26 vs 16%) were more prevalent with MB vs M, respectively. Epistaxis, fatigue and diarrhea were seen in > 15% of pts receiving M. Nausea, vomiting, diarrhea, constipation, abdominal pain, fatigue, pyrexia, anorexia, URI, arthralgia, muscle cramp, dizziness, peripheral neuropathy and headache occurred in > 15% pts receiving MB. 10 pts died on study, 9 during primary phase and 1 during extension phase. 3 deaths were the result of sepsis, the remaining 7 were due to progressive disease. Conclusions: SCIO-469, 60 mg tid, as monotherapy or in combination with Bortezomib was well tolerated. Although there were no objective responses in M (compared to 32% (11/34) in MB-including 4 patients who had failed prior bortezomib), 24% had stable disease at the end of monotherapy. Further studies to refine the dose of SCIO-469 as monotherapy and of SCIO-469 in combination with other agents are warranted.