Статті в журналах: "P53, 14-3-3"

1

Mühlmann, Gilbert, Dietmar Öfner, Matthias Zitt, Hannes M. Müller, Hans Maier, Patrizia Moser, Kurt W. Schmid, Marion Zitt, and Albert Amberger. "14-3-3 Sigma And p53 Expression in Gastric Cancer and Its Clinical Applications." Disease Markers 29, no. 1 (2010): 21–29. http://dx.doi.org/10.1155/2010/470314.

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14-3-3 sigma (σ) induces G2 arrest enabling the repair of damaged DNA. The function of 14-3-3 σ is frequently lost in tumor cells, indicating a potential tumor suppressor function. The purpose of this study was to evaluate the prognostic value of 14-3-3 σ expression in human gastric cancer. 14-3-3 σ expression was analyzed by immunohistochemistry in 157 tumor samples of patients, who underwent resection for gastric cancer. Since 14-3-3 σ is involved in the p53 network, p53 expression was detected in parallel and correlated with 14-3-3 σ. 14-3-3 σ was found to be overexpressed in 75 (47.8%) of 157 cases, the overexpression rate of p53 protein was 27.4%. 14-3-3 σ overexpression was statistically significantly associated with pT-stage (p=0.041) pN-stage (p=0.015) and UICC-stage (p=0.019) and showed a borderline significance with Lauren classification (p=0.057). Univariate survival calculations revealed a coexistent 14-3-3 σ and p53 overexpression as a significant predictor of disease-free survival. Multivariate analysis did not unfold 14-3-3 as an independent prognostic factor for disease-free survival and overall survival. Concomitant 14-3-3 σ and p53 overexpression in tumor cells of patients with gastric cancer identifies a population of patients with relatively unfavorable prognosis.

2

Yang, Heng-Yin, Yu-Ye Wen, Chih-Hsin Chen, Guillermina Lozano та Mong-Hong Lee. "14-3-3σ Positively Regulates p53 and Suppresses Tumor Growth". Molecular and Cellular Biology 23, № 20 (15 жовтня 2003): 7096–107. http://dx.doi.org/10.1128/mcb.23.20.7096-7107.2003.

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ABSTRACT The 14-3-3σ (sigma) protein, a negative regulator of the cell cycle, is a human mammary epithelium-specific marker that is downregulated in transformed mammary carcinoma cells. It has also been identified as a p53-inducible gene product involved in cell cycle checkpoint control after DNA damage. Although 14-3-3σ is linked to p53-regulated cell cycle checkpoint control, detailed mechanisms of how cell cycle regulation occurs remain unclear. Decreased expression of 14-3-3σ was recently reported in several types of carcinomas, further suggesting that the negative regulatory role of 14-3-3σ in the cell cycle is compromised during tumorigenesis. However, this possible tumor-suppressive role of 14-3-3σ has not yet been characterized. Here, we studied the link between 14-3-3σ activities and p53 regulation. We found that 14-3-3σ interacted with p53 in response to the DNA-damaging agent adriamycin. Importantly, 14-3-3σ expression led to stabilized expression of p53. In studying the molecular mechanism of this increased stabilization of p53, we found that 14-3-3σ antagonized the biological functions of Mdm2 by blocking Mdm2-mediated p53 ubiquitination and nuclear export. In addition, we found that 14-3-3σ facilitated the oligomerization of p53 and enhanced p53's transcriptional activity. As a target gene of p53, 14-3-3σ appears to have a positive feedback effect on p53 activity. Significantly, we also showed that overexpression of 14-3-3σ inhibited oncogene-activated tumorigenicity in a tetracycline-regulated 14-3-3σ system. These results defined an important p53 regulatory loop and suggested that 14-3-3σ expression can be considered for therapeutic intervention in cancers.

3

CHEN, DE-YU, DONG-FANG DAI, YE HUA та WEN-QING QI. "p53 suppresses 14-3-3γ by stimulating proteasome-mediated 14-3-3γ protein degradation". International Journal of Oncology 46, № 2 (7 листопада 2014): 818–24. http://dx.doi.org/10.3892/ijo.2014.2740.

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4

Doveston, Richard G., Ave Kuusk, Sebastian A. Andrei, Seppe Leysen, Qing Cao, Maria P. Castaldi, Adam Hendricks, et al. "Small-molecule stabilization of the p53 - 14-3-3 protein-protein interaction." FEBS Letters 591, no. 16 (August 2017): 2449–57. http://dx.doi.org/10.1002/1873-3468.12723.

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5

Rawlinson, Imogen, Carol McMenemy та David Greenhalgh. "P19 Inducible 14-3-3 sigma/stratifin ablation accelerates malignant progression in HK1.ras/fos-Δ5PTENflx transgenic mouse skin carcinogenesis". British Journal of Dermatology 189, № 1 (липень 2023): e21-e21. http://dx.doi.org/10.1093/bjd/ljad174.040.

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Abstract In human carcinogenesis, given the plethora of pathways associated with 14-3-3σ and their complex interactions, the causality of 14-3-3σ deregulation remains elusive, with both tumour suppressive and oncogenic roles. To study mechanisms driving/inhibiting skin carcinogenesis, stage-specific expression of endogenous 14-3-3σ (stratifin) was analysed in skin carcinogenesis driven by activated rasHa/fos expression (HK1.ras/fos) and ablation of phosphatase and tensin homolog (PTEN)-mediated Akt regulation (K14.creP/Δ5PTENflx) and via conditional RU486-inducible 14-3-3σ knockout (K14.creP-Δ14-3-3). Consistent with 14-3-3σ roles in the commitment of keratinocytes to differentiate, bigenic HK1.fos/Δ5PTENflx hyperplasia expressed 14-3-3σ in basal layers and paralleled keratin K1 expression which appeared alongside elevated p53/p21 to increase keratinocyte differentiation leading to a keratoacanthoma (KA) aetiology. Trigenic HK1.ras/fos-Δ5PTENflx hyperplasia/papillomas also displayed increased basal-layer 14-3-3σ, suggesting attempts to protect basal layer p53 tumour suppressor gene function, given that 14-3-3σ acts as a chaperone protein to remove/relocate MDM2 for degradation, thus maintaining p53 levels. With time, HK1.ras/fos-Δ5PTENflx papillomas exhibited reduced p53 and increased p-MDM2166 activity in basal layers, which coincided with malignant conversion. Surprisingly, despite this p53 loss, 14-3-3σ expression persisted in well-differentiated squamous cell carcinomas (wdSCC) and, alongside elevated p21, appeared to limit further malignant progression via inhibiting p-Akt1473 expression. To further assess causality, 14-3-3σ functions were ablated in this model via an RU486-inducible cre/loxP system expressed from a keratin 14 (K14) promoter (K14.creP-Δ14-3-3σ). In bigenic HK1.fos-Δ14-3-3σ, preliminary data suggest loss of 14-3-3σ functions resulted in increased hyperplasia and keratosis similar to that observed in bigenic HK1.fos/Δ5PTENflx hyperplasia. Functional 14-3-3σ ablation in HK1.ras.fos/Δ5PTENflx/Δ14-3-3σflx genotypes apparently failed to accelerate papillomatogenesis, suggesting elements of redundancy in terms of tumour promotion; however, loss of 14-3-3σ facilitated increased p-MDM2166 and p53 loss, resulting in malignant conversion with progression to aggressive SCC. Collectively, these data suggest that 14-3-3σ/stratifin exerts suppressive roles in papillomatogenesis via MDM2/p53-dependent mechanisms, while persistent expression in wdSCCs suggests p53-independent scenarios that may involve p21-mediated Akt1 inhibition. However, if ablated, this limit of early-stage malignant progression is lost and 14-3-3σ loss leads to rapid progression to aggressive, p21-negative SCCs exhibiting uniform p-Akt1473activation.

6

Yang, Wensheng, David T. Dicker, Jiandong Chen, and Wafik S. El-Deiry. "CARPs enhance p53 turnover by degrading 14-3-3σ and stabilizing MDM2." Cell Cycle 7, no. 5 (March 2008): 670–82. http://dx.doi.org/10.4161/cc.7.5.5701.

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7

Rajagopalan, Sridharan, Robert S. Sade, Fiona M. Townsley, and Alan R. Fersht. "Mechanistic differences in the transcriptional activation of p53 by 14-3-3 isoforms." Nucleic Acids Research 38, no. 3 (November 20, 2009): 893–906. http://dx.doi.org/10.1093/nar/gkp1041.

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8

Schumacher, Benjamin, Justine Mondry, Philipp Thiel, Michael Weyand, and Christian Ottmann. "Structure of the p53 C-terminus bound to 14-3-3: Implications for stabilization of the p53 tetramer." FEBS Letters 584, no. 8 (March 3, 2010): 1443–48. http://dx.doi.org/10.1016/j.febslet.2010.02.065.

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9

Waterman, Matthew J. F., Elena S. Stavridi, Jennifer L. F. Waterman, and Thanos D. Halazonetis. "ATM-dependent activation of p53 involves dephosphorylation and association with 14-3-3 proteins." Nature Genetics 19, no. 2 (June 1998): 175–78. http://dx.doi.org/10.1038/542.

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10

Montano, Ximena. "Common amino acid sequence motifs in p53, 14-3-3 and Akt protein families." FEBS Letters 507, no. 2 (October 18, 2001): 237–40. http://dx.doi.org/10.1016/s0014-5793(01)02903-9.

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11

Lee, Mong-Hong, та Guillermina Lozano. "Regulation of the p53-MDM2 pathway by 14-3-3 σ and other proteins". Seminars in Cancer Biology 16, № 3 (червень 2006): 225–34. http://dx.doi.org/10.1016/j.semcancer.2006.03.009.

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12

Hardman-Carter, Rebecca, Revvekka Lefkati, Carol McMenemy, and David Greenhalgh. "P10 Inducible 14-3-3 sigma/stratifin ablation cooperates with rasHa activation to accelerate papillomatogenesis and induce malignant conversion in transgenic mouse skin carcinogenesis." British Journal of Dermatology 189, no. 1 (July 2023): e17-e18. http://dx.doi.org/10.1093/bjd/ljad174.032.

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Abstract In carcinogenesis, the 14-3-3σ isoform (stratifin) is implicated by being downregulated in a mode of classic tumour suppression gene (TSG) loss and also via elevated oncogenic roles; with both scenarios appearing to be hallmarks of 14-3-3σ deregulation, depending on tumour stage or context. Mouse skin models highlight tumour-suppressive roles, as the Er/Er+/– repeated epilation stain possesses germline mutations that result in hyperplasia, failed follicular differentiation and susceptibility to squamous cell carcinoma (SCC). In transgenic models, 14-3-3σ knockout supports early roles, resulting in rapid papilloma formation in classic two-stage DMBA/TPA chemical carcinogenesis; however, our previous studies in this model demonstrated targeted overexpression of 14-3-3σ led to SCC of a follicular origin in collaboration with Fos and well-differentiated SCC in collaboration with rasHa. Therefore, to study mechanisms driving/inhibiting skin carcinogenesis, stage-specific expression of endogenous 14-3-3σ (stratifin) was analysed in early skin carcinogenesis driven by activated rasHa expression (HK1.ras) and subsequently via conditional RU486-inducible 14-3-3σ knockout (K14.creP-Δ14-3-3σ). Consistent with 14-3-3σ roles previously observed in epidermal differentiation, HK1.ras hyperplasia and early papillomas displayed elevated 14-3-3σ expression in suprabasal keratinocytes and in occasional K1-positive basal keratinocytes as they committed to differentiate. Older HK1.ras mice exhibited increasing 14-3-3σ positivity in papilloma basal layers, suggesting attempts to protect basal-layer p53 TSG function, given that 14-3-3σ acts as a chaperone protein to remove/relocate MDM2 for degradation, thus maintaining p53 levels. Indeed, such papillomas expressed activated p-MDM2166 confined to suprabasal layers, resulting in strong basal layer p53 expression and thus HK1.ras papillomas lacked malignant conversion. In mice where 14-3-3σ functions were ablated via an RU486-inducible Cre/loxP system expressed from a keratin 14 (K14) promoter (K14.creP-Δ14-3-3σ), treated HK1.ras-K14.Δ14-3-3σ mice exhibited a rapid papillomatogenesis and produced larger papillomas. These papillomas also exhibited rapid conversion to malignancy, associated with increased activated p-MDM2166 expression in basal layers and resultant p53 loss. These observations suggest that 14-3-3σ plays tumour suppressive roles involving p53 protection, where failure to regulate MDM2 activity led to p53 loss and susceptibility to malignant conversion. P11 Abstract withdrawn.

13

Aktary, Z., S. Kulak, J. Mackey, N. Jahroudi, and M. Pasdar. "Plakoglobin interacts with the transcription factor p53 and regulates the expression of 14-3-3." Journal of Cell Science 126, no. 14 (May 17, 2013): 3031–42. http://dx.doi.org/10.1242/jcs.120642.

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14

Rajagopalan, S., A. M. Jaulent, M. Wells, D. B. Veprintsev, and A. R. Fersht. "14-3-3 activation of DNA binding of p53 by enhancing its association into tetramers." Nucleic Acids Research 36, no. 18 (September 6, 2008): 5983–91. http://dx.doi.org/10.1093/nar/gkn598.

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15

Jin, Yun-Hye, Yeon-Jin Kim, Dae-Won Kim, Kwang-Hyun Baek, Bok Yun Kang, Chang-Yeol Yeo та Kwang-Youl Lee. "Sirt2 interacts with 14-3-3 β/γ and down-regulates the activity of p53". Biochemical and Biophysical Research Communications 368, № 3 (квітень 2008): 690–95. http://dx.doi.org/10.1016/j.bbrc.2008.01.114.

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16

Okamoto, Koji, Kenji Kashima, Yaron Pereg, Michiko Ishida, Satomi Yamazaki, Ayumi Nota, Amina Teunisse, et al. "DNA Damage-Induced Phosphorylation of MdmX at Serine 367 Activates p53 by Targeting MdmX for Mdm2-Dependent Degradation." Molecular and Cellular Biology 25, no. 21 (November 1, 2005): 9608–20. http://dx.doi.org/10.1128/mcb.25.21.9608-9620.2005.

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ABSTRACT Understanding how p53 activity is regulated is crucial in elucidating mechanisms of cellular defense against cancer. Genetic data indicate that Mdmx as well as Mdm2 plays a major role in maintaining p53 activity at low levels in nonstressed cells. However, biochemical mechanisms of how Mdmx regulates p53 activity are not well understood. Through identification of Mdmx-binding proteins, we found that 14-3-3 proteins are associated with Mdmx. Mdmx harbors a consensus sequence for binding of 14-3-3. Serine 367 (S367) is located within the putative binding sequence for 14-3-3, and its substitution with alanine (S367A) abolishes binding of Mdmx to 14-3-3. Transfection assays indicated that the S367A mutation, in cooperation with Mdm2, enhances the ability of Mdmx to repress the transcriptional activity of p53. The S367A mutant is more resistant to Mdm2-dependent ubiquitination and degradation than wild-type Mdmx, and Mdmx phosphorylated at S367 is preferentially degraded by Mdm2. Several types of DNA damage markedly enhance S367 phosphorylation, coinciding with increased binding of Mdmx to 14-3-3 and accelerated Mdmx degradation. Furthermore, promotion of growth of normal human fibroblasts after introduction of Mdmx is enhanced by the S367 mutation. We propose that Mdmx phosphorylation at S367 plays an important role in p53 activation after DNA damage by triggering Mdm2-dependent degradation of Mdmx.

17

Chan, Timothy A., Paul M. Hwang, Heiko Hermeking, Kenneth W. Kinzler, and Bert Vogelstein. "Cooperative effects of genes controlling the G₂/M checkpoint." Genes & Development 14, no. 13 (July 1, 2000): 1584–88. http://dx.doi.org/10.1101/gad.14.13.1584.

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It is believed that multiple effectors independently control the checkpoints permitting transitions between cell cycle phases. However, this has not been rigorously demonstrated in mammalian cells. The p53-induced genes p21 and 14-3-3ς are each required for the G2 arrest and allow a specific test of this fundamental tenet. We generated human cells deficient in bothp21 and 14-3-3ς and determined whether the double knockout was more sensitive to DNA damage than either single knockout.p21−/−14-3-3ς−/− cells were significantly more sensitive to DNA damage or to the exogenous expression of p53 than cells lacking only p21 or only 14-3-3ς. Thus, p21 and 14-3-3ς play distinct but complementary roles in the G2/M checkpoint, and help explain why genes at the nodal points of growth arrest pathways, like p53, are the targets of mutation in cancer cells.

18

Muñoz-Fontela, Cesar, Laura Marcos-Villar, Pedro Gallego, Javier Arroyo, Marco Da Costa, Karen M. Pomeranz, Eric W. F. Lam, and Carmen Rivas. "Latent Protein LANA2 from Kaposi's Sarcoma-Associated Herpesvirus Interacts with 14-3-3 Proteins and Inhibits FOXO3a Transcription Factor." Journal of Virology 81, no. 3 (November 15, 2006): 1511–16. http://dx.doi.org/10.1128/jvi.01816-06.

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ABSTRACT The Kaposi's sarcoma-associated herpesvirus latent protein LANA2 has been suggested to have an important role in the transforming activity of the virus based on its capacity to inhibit p53 and PKR-dependent apoptosis as well as the interferon-dependent response. Here, we describe a novel interaction between LANA2 and both the phosphoserine/phosphothreonine-binding 14-3-3 proteins and the transcription factor FOXO3a. In addition, our results indicate that LANA2 inhibits the transcriptional activity of FOXO3a and blocks the G2/M arrest induced by 14-3-3 protein overexpression. These results suggest a novel mechanism by which LANA2 may promote tumorigenesis.

19

Kuusk, Ave, Helen Boyd, Hongming Chen, and Christian Ottmann. "Small-molecule modulation of p53 protein-protein interactions." Biological Chemistry 401, no. 8 (July 28, 2020): 921–31. http://dx.doi.org/10.1515/hsz-2019-0405.

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AbstractSmall-molecule modulation of protein-protein interactions (PPIs) is a very promising but also challenging area in drug discovery. The tumor suppressor protein p53 is one of the most frequently altered proteins in human cancers, making it an attractive target in oncology. 14-3-3 proteins have been shown to bind to and positively regulate p53 activity by protecting it from MDM2-dependent degradation or activating its DNA binding affinity. PPIs can be modulated by inhibiting or stabilizing specific interactions by small molecules. Whereas inhibition has been widely explored by the pharmaceutical industry and academia, the opposite strategy of stabilizing PPIs still remains relatively underexploited. This is rather interesting considering the number of natural compounds like rapamycin, forskolin and fusicoccin that exert their activity by stabilizing specific PPIs. In this review, we give an overview of 14-3-3 interactions with p53, explain isoform specific stabilization of the tumor suppressor protein, explore the approach of stabilizing the 14-3-3σ-p53 complex and summarize some promising small molecules inhibiting the p53-MDM2 protein-protein interaction.

20

Lee, Jun-Ho, та Hua Lu. "14-3-3γ Inhibition of MDMX-mediated p21 Turnover Independent of p53". Journal of Biological Chemistry 286, № 7 (9 грудня 2010): 5136–42. http://dx.doi.org/10.1074/jbc.m110.190470.

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21

Yang, Huiling, Ruiying Zhao та Mong-Hong Lee. "14-3-3σ, a p53 regulator, suppresses tumor growth of nasopharyngeal carcinoma". Molecular Cancer Therapeutics 5, № 2 (лютий 2006): 253–60. http://dx.doi.org/10.1158/1535-7163.mct-05-0395.

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22

Hermeking, Heiko, Christoph Lengauer, Kornelia Polyak, Tong-Chuan He, Lin Zhang, Sam Thiagalingam, Kenneth W. Kinzler та Bert Vogelstein. "14-3-3σ Is a p53-Regulated Inhibitor of G2/M Progression". Molecular Cell 1, № 1 (грудень 1997): 3–11. http://dx.doi.org/10.1016/s1097-2765(00)80002-7.

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23

Liu, Nan, Hongli Yang та Liangui Yang. "Modeling the roles of 14-3-3 σ and Wip1 in p53 dynamics and programmed cell death*". Communications in Theoretical Physics 73, № 8 (21 червня 2021): 085602. http://dx.doi.org/10.1088/1572-9494/abfd2a.

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24

Wang, Moyu, Hongmei Li, Xiyu Sun, Jianhua Qiu, Changhua Jing, Huiyue Jia, Yujie Guo та Huijun Guo. "J Subgroup Avian Leukosis Virus Strain Promotes Cell Proliferation by Negatively Regulating 14-3-3σ Expressions in Chicken Fibroblast Cells". Viruses 15, № 2 (31 січня 2023): 404. http://dx.doi.org/10.3390/v15020404.

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This study focuses on clarifying the regulation of chicken 14-3-3σ protein on the fibrous histiocyte proliferation caused by ALV-J-SD1005 strain infection. DF-1 cells were inoculated with 102 TCID50 of ALV-J-SD1005 strain; the cell proliferation viability was dramatically increased and 14-3-3σ expressions were dramatically decreased within 48 hours after inoculation. Chicken 14-3-3σ over-expression could significantly decrease the cell proliferation and the ratio of S-phase cells, but increase the ratio of G2/M-phase cells in ALV-J-infected DF-1 cells; by contrast, chicken 14-3-3σ knockdown expression could cause the opposite effects. Additionally, chicken 14-3-3σ over-expression could also dramatically down-regulate the expressions of CDK2/CDC2, but up-regulate p53 expressions in the DF-1 cells; in contrast, the knockdown expression could significantly increase the expressions of CDK2/CDC2 and decrease p53 expressions. It can be concluded that chicken 14-3-3σ can inhibit cell proliferation and cell cycle by regulating CDK2/CDC2/p53 expressions in ALV-J-infected DF1 cells. ALV-J-SD1005 strain can promote cell proliferation by reducing 14-3-3σ expressions. This study helps to clarify the forming mechanism of acute fibrosarcoma induced by ALV-J infection.

25

Ohtani, Shoichiro, Shunsuke Kagawa, Yasuhisa Tango, Tatsuo Umeoka, Naoyuki Tokunaga, Yousuke Tsunemitsu, Jack A. Roth, Yoichi Taya, Noriaki Tanaka, and Toshiyoshi Fujiwara. "Quantitative analysis of p53-targeted gene expression and visualization of p53 transcriptional activity following intratumoral administration of adenoviral p53 in vivo." Molecular Cancer Therapeutics 3, no. 1 (January 1, 2004): 93–100. http://dx.doi.org/10.1158/1535-7163.93.3.1.

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Abstract To analyze the mechanism of the antitumor effect of an adenoviral vector expressing the p53 tumor suppressor (Ad-p53) in vivo, we quantitatively assessed p53-targeted gene expression and visualized transcriptional activity of p53 in tumors in nude mice treated with Ad-p53. Human lung cancer (H1299) xenografts established in nude mice were treated by intratumoral administration of Ad-p53. The levels of expression of exogenous p53 and p53-targeted genes p21, MDM2, Noxa, and p53AIP1 were quantified by real-time reverse transcription-PCR (RT-PCR) and induction of apoptosis was observed histochemically on days 1–3, 7, and 14 after treatment. Expression of mRNA of exogenous p53 and p53-targeted genes (except p53AIP1) was at its maximum 1 day after Ad-p53 treatment and then decreased rapidly; apoptosis was evident in situ 2–3 days after treatment. We developed a noninvasive and simple method for monitoring the transcriptional activity of exogenous p53 following intratumoral administration of Ad-p53 in nude mice. We established H1299 cells that express the green fluorescent protein (GFP) reporter gene under the control of p53-responsive p21 promoter (i.e., the p53R-GFP reporter system). Xenografts of these cells in nude mice were treated by intratumoral administration of Ad-p53, and the transcriptional activity of exogenous p53 could be visualized as intratumoral GFP expression in real time by 3-CCD camera. Expression of GFP was maximal 3 days after treatment and decreased remarkably by 7 days after treatment. We demonstrated that Ad-p53 treatment rapidly induced p53-targeted genes and apoptosis in tumors and succeeded in visualizing p53 transcriptional activity in vivo. We also found that Ad-p53 infection induced phosphorylation of p53 at Ser46 in p53-sensitive H1299 cells in vitro but not in p53-resistant H226Br cells, suggesting that phosphorylation of Ser46 is involved in p53-dependent apoptosis. Our data indicate that quantitative analysis of p53-targeted gene expression by real-time quantitative RT-PCR and visualization of p53 transcriptional activity in fresh xenografts by using the p53R-GFP reporter system may be useful in assessing the mechanisms of the antitumor effects of Ad-p53 and novel therapeutic approaches.

26

Pereg, Yaron, Suzanne Lam, Amina Teunisse, Sharon Biton, Erik Meulmeester, Leonid Mittelman, Giacomo Buscemi, et al. "Differential Roles of ATM- and Chk2-Mediated Phosphorylations of Hdmx in Response to DNA Damage." Molecular and Cellular Biology 26, no. 18 (September 15, 2006): 6819–31. http://dx.doi.org/10.1128/mcb.00562-06.

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ABSTRACT The p53 tumor suppressor plays a major role in maintaining genomic stability. Its activation and stabilization in response to double strand breaks (DSBs) in DNA are regulated primarily by the ATM protein kinase. ATM mediates several posttranslational modifications on p53 itself, as well as phosphorylation of p53's essential inhibitors, Hdm2 and Hdmx. Recently we showed that ATM- and Hdm2-dependent ubiquitination and subsequent degradation of Hdmx following DSB induction are mediated by phosphorylation of Hdmx on S403, S367, and S342, with S403 being targeted directly by ATM. Here we show that S367 phosphorylation is mediated by the Chk2 protein kinase, a downstream kinase of ATM. This phosphorylation, which is important for subsequent Hdmx ubiquitination and degradation, creates a binding site for 14-3-3 proteins which controls nuclear accumulation of Hdmx following DSBs. Phosphorylation of S342 also contributed to optimal 14-3-3 interaction and nuclear accumulation of Hdmx, but phosphorylation of S403 did not. Our data indicate that binding of a 14-3-3 dimer and subsequent nuclear accumulation are essential steps toward degradation of p53's inhibitor, Hdmx, in response to DNA damage. These results demonstrate a sophisticated control by ATM of a target protein, Hdmx, which itself is one of several ATM targets in the ATM-p53 axis of the DNA damage response.

27

Oldfield, Christopher J., Jingwei Meng, Jack Y. Yang, Mary Qu Yang, Vladimir N. Uversky, and A. Keith Dunker. "Flexible nets: disorder and induced fit in the associations of p53 and 14-3-3 with their partners." BMC Genomics 9, Suppl 1 (2008): S1. http://dx.doi.org/10.1186/1471-2164-9-s1-s1.

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28

Schumacher, Benjamin, Justine Mondry, Philipp Thiel, Michael Weyand та Christian Ottmann. "Binary complex of 14-3-3σ/p53 pT387-peptide and implications for stabilization". Acta Crystallographica Section A Foundations of Crystallography 66, a1 (29 серпня 2010): s148—s149. http://dx.doi.org/10.1107/s0108767310096698.

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29

Brownlee, Noel A., L. Allen Perkins, Will Stewart, Beth Jackle, Mark J. Pettenati, Patrick P. Koty, Samy S. Iskandar, and A. Julian Garvin. "Recurring Translocation (10;17) and Deletion (14q) in Clear Cell Sarcoma of the Kidney." Archives of Pathology & Laboratory Medicine 131, no. 3 (March 1, 2007): 446–51. http://dx.doi.org/10.5858/2007-131-446-rtadqi.

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Abstract Context.—Clear cell sarcoma of the kidney (CCSK) is a prognostically unfavorable renal neoplasm of childhood. Previous cytogenetic studies of CCSK have reported balanced translocations t(10;17)(q22;p13) and t(10;17)(q11; p12). Although the tumor suppressor gene p53 is located at the chromosome 17p13 breakpoint, p53 abnormalities are rarely present in these tumors. Objective.—To identify cytogenetic abnormalities in CCSK and correlate these findings with other clinicopathologic parameters. Design.—A retrospective review of CCSK patients from 1990 to 2005 was conducted at our medical center. We performed clinical and histologic review, p53 immunohistochemical and classic cytogenetics (or ploidy analysis), and p53 fluorescence in situ hybridization analyses. Results.—Five male patients (age range, 6 months to 4 years) were identified with cytogenetic abnormalities. Of 3 cytogenetically informative cases, one revealed a clonal balanced translocation t(10;17)(q22;p13) and an interstitial deletion of chromosome 14, del(14)(q24.1q31.1), and the other 2 patients had normal karyotypes. Fluorescence in situ hybridization for p53 in the t(10;17) case revealed no deletion. Immunohistochemical evaluation of p53 demonstrated lack of nuclear protein accumulation in all cases. Conclusions.—Together with the published literature, our results indicate that translocation (10;17) and interstitial deletions of chromosome 14q are recurring cytogenetic lesions in CCSK. To date, 3 cases of CCSK or “sarcomatoid Wilms tumors” have been reported to exhibit t(10;17). One previously reported case of CCSK contained deletion 14q. Results of p53 immunohistochemistry and/or p53 fluorescence in situ hybridization in this report suggest lack of mutations or deletions of this tumor suppressor in these CCSK cases. The t(10;17) breakpoint and deletion of chromosome 14q24 suggest that other genes are involved in tumor pathogenesis.

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Gu, Yanyan, Jonathan L. Kaufman, Lawrence H. Boise та Sagar Lonial. "Validation of the Function of 14-3-3 ζ in Multiple Myeloma (MM)". Blood 118, № 21 (18 листопада 2011): 1369. http://dx.doi.org/10.1182/blood.v118.21.1369.1369.

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Abstract Abstract 1369 The 14-3-3 protein family includes seven members, β, γ, ε, η, σ, τ and ζ. With over 200 binding partners, 14-3-3 proteins act as integrators of diverse cell signaling pathways and participate in metabolism, cell cycle regulation, survival and apoptosis. 14-3-3ζ has been implicated in many cancers such as hepatocellular carcinoma, gastric cancer, breast cancer, lung carcinoma and lymphoma. However, the role of 14-3-3ζ in MM has not been extensively explored. Preliminary data from an affymatrix GEP profile of normal plasma cells (NPC), MGUS, Smoldering myeloma (SM) or multiple myeloma (MM) demonstrates statistically increased expression of 14-3-3 ζ in the transition between MGUS and SM. Among patients with newly diagnosed symptomatic MM, 14-3-3 ζ expression appears to be higher in the higher risk genetic subsets. These data suggest 14-3-3ζ plays a prominent role in the biology of MM especially among high risk myeloma patients. In order to identify the impact of 14-3-3 ζ signaling on MM proliferation and survival, we developed 14-3-3ζ silenced and over expressing stable cell lines to interrogate the biological role of 14-3-3ζ in MM. Using a library of human MM cell lines, we found that 14-3-3ζ is universally expressed in all MM cell lines examined. Knockdown of 14-3-3ζ significantly inhibits cell growth and proliferation in LP1 and U266 cells, which is partly related to G1 cell cycle arrest. Relevant signaling proteins such as Mcl-1, Bcl2, phospho-Akt and CDK6 decrease after silencing 14-3-3ζ. Furthermore, we performed gene expression profiling of LP1 scrambled and knockdown stable cell lines in order to identify key changes in gene regulation that may be mediated via 14-3-3ζ. The GEP data suggests that 14-3-3ζ is responsible for but not limited to several important signaling pathways, such as glycolysis/gluconeogenesis, p53 Signaling, NRF2-mediated oxidative stress response and death receptor signaling. In addition, we evaluated the effect of 14-3-3ζ expression on the drug sensitivity to commonly used chemotherapeutic compounds in MM treatment, such as bortezomib, etoposide, dexamethasone, melphalan, lenalidomide, doxorubicin and romidepsin. Knockdown 14-3-3ζ sensitizes cells to romidepsin- induced apoptosis, as demonstrated by Annexin V staining and western blot assay for caspase cleavage. However, bortezomib- induced apoptosis is significantly inhibited when 14-3-3ζ is silenced. Bortezomib (5nM)-induced apoptosis decreased from 37% in LP1 cells expressing shRNA with scrambled sequence to 14% in LP1 cells where 14-3-3 ζ is silenced. Moreover, 14-3-3ζ knockdown effectively inhibits bortezomib induced NOXA upregulation, suggesting a possible new molecular mechanism for the effects of 14-3-3ζ in bortezomib mediated apoptosis. Taken together, our work reveals the important biological function of 14-3-3ζ in MM growth, survival and proliferation; the data also provides valuable information for the development of new therapeutic strategies facilitating drug sensitivity and overcoming drug resistance. Disclosures: Kaufman: Millenium: Consultancy; Onyx Pharmaceuticals: Consultancy; Novartis: Consultancy; Keryx: Consultancy; Merck: Research Funding; Celgene: Research Funding. Lonial:Onyx: Consultancy; Bristol-Myers Squibb: Consultancy; Novartis: Consultancy; Celgene: Consultancy; Millennium Pharmaceuticals, Inc.: Consultancy; Merck: Consultancy.

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Nagappan, Arulkumar, Hyeon Soo Park, Kwang Il Park, Gyeong Eun Hong, Silvia Yumnam, Ho Jeong Lee, Mun Ki Kim, et al. "Helicobacter pylori infection combined with DENA revealed altered expression of p53 and 14-3-3 isoforms in Gulo−/− mice." Chemico-Biological Interactions 206, no. 2 (November 2013): 143–52. http://dx.doi.org/10.1016/j.cbi.2013.09.002.

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Benzinger, Anne, Nemone Muster, Heike B. Koch, John R. Yates та Heiko Hermeking. "Targeted Proteomic Analysis of 14-3-3ς, a p53 Effector Commonly Silenced in Cancer". Molecular & Cellular Proteomics 4, № 6 (18 березня 2005): 785–95. http://dx.doi.org/10.1074/mcp.m500021-mcp200.

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Danes, Christopher G., Shannon L. Wyszomierski, Jing Lu, Christopher L. Neal, Wentao Yang та Dihua Yu. "14-3-3ζ Down-regulates p53 in Mammary Epithelial Cells and Confers Luminal Filling". Cancer Research 68, № 6 (13 березня 2008): 1760–67. http://dx.doi.org/10.1158/0008-5472.can-07-3177.

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Lee, Ming Kei, and Kanaga Sabapathy. "Phosphorylation at Carboxyl-Terminal S373 and S375 Residues and 14-3-3 Binding Are Not Required for Mouse p53 Function." Neoplasia 9, no. 9 (September 2007): 690–98. http://dx.doi.org/10.1593/neo.07511.

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Zhang, Bo, Bo Zhou, Guihong Huang, Jing'an Huang, Xiaoxin Lin, Zonghuai Li, Yuanchu Lian, Qiujie Huang, and Yong Ye. "Nitidine chloride inhibits G2/M phase by regulating the p53/14-3-3 Sigma/CDK1 axis for hepatocellular carcinoma treatment." Heliyon 10, no. 1 (January 2024): e24012. http://dx.doi.org/10.1016/j.heliyon.2024.e24012.

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Wu, Qiao, Hua Fan, Ren Lang, Xianliang Li, Xingmao Zhang, Shaocheng Lv та Qiang He. "Overexpression of 14-3-3σ Modulates Cholangiocarcinoma Cell Survival by PI3K/Akt Signaling". BioMed Research International 2020 (23 червня 2020): 1–9. http://dx.doi.org/10.1155/2020/3740418.

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The protein 14-3-3σ is involved in numerous cellular processes through its ability to bind phosphorylated serine/threonine residues. It is a key regulator of the cell cycle involving in G2 arrest by p53. Deregulation of 14-3-3σ expression has been associated with a large variety of human cancers. However, its physiological function and therapeutic significance have rarely been investigated in cholangiocarcinoma. Using immunohistochemistry (IHC), we evaluated 14-3-3σ expression in 65 human extrahepatic cholangiocarcinomas. As a result, we found that 14-3-3σ is expressed in the tissue of 56 patients (86.2%), and its expression is positively correlated with tumor size, lymph node metastasis, and tumor stage. We also explored the significance of 14-3-3σ and found that 14-3-3σ exerts cell type-dependent effects on cell proliferation through PI3K/Akt signaling in both in vitro and in vivo xenograft models. These results suggest that 14-3-3σ assumes a constitutive role in tumorigenesis rather than acting as a cell cycle regulator in cholangiocarcinoma, which makes 14-3-3σ a new potential target for therapeutic intervention.

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Tolcher, Anthony W., Desiree Hao, Johann de Bono, Alex Miller, Amita Patnaik, Lisa A. Hammond, Leslie Smetzer, et al. "Phase I, Pharmacokinetic, and Pharmacodynamic Study of Intravenously Administered Ad5CMV-p53, an Adenoviral Vector Containing the Wild-Type p53 Gene, in Patients With Advanced Cancer." Journal of Clinical Oncology 24, no. 13 (May 1, 2006): 2052–58. http://dx.doi.org/10.1200/jco.2005.03.6756.

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Purpose The purpose of this study was to assess the feasibility of administering Ad5CMV-p53, an adenoviral vector containing the wild-type p53 gene to patients with advanced malignancies, characterize the pertinent pharmacokinetic parameters, identify evidence of viral uptake in both normal and tumor tissue, and seek evidence of antitumor activity. Methods Patients were treated with escalating doses of Ad5CMV-p53 intravenously over 30 minutes on days 1, 2, and 3, every 28 days. The clearance of circulating Ad5CMV-p53 (INGN 201) DNA was characterized in the plasma and paired tumor and skin biopsies were performed in patients treated at the two highest dose levels to assess vector uptake into tissues. Results Seventeen patients received 36 courses of Ad5CMV-p53 at doses ranging from 3 × 1010 to 3 × 1012 virus particles (vp). Fatigue, nausea, vomiting, and fever were common, but rarely severe. Abnormalities of coagulation parameters, including decreases in fibrinogen and increases in fibrin degradation products at 3 × 1012vp, precluded additional dose escalation. Ad5CMV-p53 DNA could be detected in the plasma by polymerase chain reaction assay in the majority of patients at 14 days and 28 days at doses of 3 × 1010 and higher. Six patients treated at 1 × 1012vp and 3 × 1012vp dose levels had Ad5CMV-p53 DNA detected within paired tumor tissue collected day 4. Conclusion Ad5CMV-p53 can be safely and repetitively administered up to 1 × 1012vp intravenously daily for 3 consecutive days. The absence of severe toxicities, the presence of circulating adenovirus 24 hours after administration, and detectable p53 transgene within tumor tissue distant from the site of administration demonstrates that systemic therapy with this adenoviral vector containing p53 is feasible.

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Zhang, Yiwei, Yitian Zha, and Hua Lu. "Abstract 2377: Impairment of p53-activating pathways accelerates liver cancer initiation partially through MTHFD1L-mediated 1C metabolism." Cancer Research 82, no. 12_Supplement (June 15, 2022): 2377. http://dx.doi.org/10.1158/1538-7445.am2022-2377.

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Abstract Hepatocellular carcinoma (HCC) takes several decades to develop from premalignant lesions in chronically damaged livers and is often detected at a later stage; thus, prevention is of particular importance. HCC originates from differentiated hepatocytes. Previous studies have shown that inhibition of the tumor suppressor p53 is required for the differentiated hepatocytes to acquire the features that are needed for their conversion to HCC progenitor cells (HcPCs). However, the initiation of p53 response to de-differentiation of damaged hepatocytes is largely unclear. p53 is tightly controlled by MDM2 and MDMX. We and others have previously demonstrated that multiple stresses can trigger the binding of 14-3-3 to phosphorylated MDMX, or ribosomal proteins L5 and L11 to MDM2, to further disrupt the MDMX- or MDM2-p53 association and lead to p53 activation. This was validated by two animal models, MDM2C305F and MDMX3SA knock-in mice that are defective in 14-3-3-MDMX and L5/L11-MDM2 interactions, respectively. By crossing these two mouse lines, we generated a double knock-in (DKI) mouse line. With this line, we found that carcinogen DEN-induced HCC occurrence is significantly higher in MDM2C305F-MDMX3SA -DKI mice, and HcPCs isolated from DEN-treated DKI mice display significantly more stem cell- and malignancy- properties and higher tumorigenesis when introduced into mouse livers. Furthermore, we found that MTHFD1L, a monofunctional tetrahydrofolate synthase required for mitochondrial 1-carbon (1C) metabolism, is transcriptionally suppressed by p53 and exerts a critical effect on the accelerated HCC initiation in DKI mice. Taken together, these results demonstrate a crucial role of these two p53-activating pathways in preventing HCC initiation by controlling the mitochondrial 1C- metabolism. Citation Format: Yiwei Zhang, Yitian Zha, Hua Lu. Impairment of p53-activating pathways accelerates liver cancer initiation partially through MTHFD1L-mediated 1C metabolism [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2377.

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Sharma, Balkrishan, Duaa Mureb, Sumit Murab, Leah A. Rosenfeldt, Brenton J. Francisco, Alexander A. Boucher, Rachel Cantrell, et al. "Fibrinogen Activates FAK to Promote the Colorectal Adenocarcinoma Growth." Blood 134, Supplement_1 (November 13, 2019): 1111. http://dx.doi.org/10.1182/blood-2019-130497.

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Along with other proteins in the coagulation cascade, including tissue factor and thrombin, fibrinogen has been shown to promote tumor metastasis across numerous cancer types. However, the role of fibrin(ogen) in primary tumor growth is context dependent and not universally important. One cancer strongly dependent on fibrin(ogen) for primary tumor growth is colorectal cancer (CRC), but the mechanisms by which fibrinogen supports colon cancer growth are not well understood. To delineate the mechanism of fibrin(ogen)-supported tumor growth, we implanted C57BL/6-derived murine colon cancer cells (MC38) into the dorsal subcutis of syngeneic mice with specific deletions/alteration in fibrinogen or FXIII-deficiency. Complete fibrinogen deficiency significantly limited the growth of colon cancer cells. However, the imposition of FXIII-deficiency or specific mutations in fibrinogen that 1) prevent the formation of fibrin polymer (FibAEK), limit fibrin(ogen) binding to the integrin αMβ2 (Fibɣ390-396A), or remove the ɣ chain binding motif for the platelet integrin αIIbβ3 (FibɣΔ5) had no impact on colon cancer growth. To explore the mechanisms coupling fibrin(ogen) to colon cancer growth using a nonbiased approach, we performed RNA-Seq analyses of murine CRC tumors harvested from Fib+ and Fib- mice. We detected significant differences in the expression of 214 genes (128 downregulated and 86 upregulated) involved in cellular proliferation, survival, migration and metabolism. Notably, Stratifin (SFN), which encodes 14-3-3-σ, was one of the genes found to be highly upregulated in tumors from Fib- mice relative to Fib+ mice. 14-3-3-σ is a potent cell cycle regulator and it is also known to stabilize p53, which ultimately inhibits tumor growth. In a separate validation cohort, we observed significantly increased protein expression of 14-3-3-σ and its upstream and downstream targets (i.e., p53, p21 and p27) in tumors harvested from Fib- mice relative to controls. We also compared FAK activation, a key negative regulator of p53, in tumors from Fib+ and Fib- mice. FAK was inactive in tumors from Fib- mice, as indicated by lack of phosphorylation at tyrosine 397 (p-FAK Tyr397). Also, MDM2 was less phosphorylated at Ser166 in Fib- tumors, suggesting that p53 is not degraded by MDM2 in the absence of fibrinogen. Taken together, these data suggest that fibrin(ogen)-mediated downregulation of p53 and other targets via FAK activation and downregulation of 14-3-3-σ results in senescence of CRC cells. Consistent with this view, Ki67 positive nuclei were significantly less in tumor from Fib- mice relative to controls We also observed senescence-associated-β-galactosidase (SA-β-gal) activity in the tumors from Fib- mice, but not those from Fib+ animals. Furthermore, NMR-based metabolomics analyses demonstrated significantly less NAD+ and lactate levels in tumors from Fib- mice, which further confirms that fibrinogen deficiency hampers proliferation by inhibiting major metabolic pathways. In order to determine if fibrinogen-mediated support of CRC growth is tumor cell intrinsic, we compared MC38 growth in the 3D bioprinted matrices consisting of fibrin or albumin. MC38 cells showed a higher proliferation rate in the fibrinogen printed 3D environment compared to the albumin environment. These findings suggest that fibrin(ogen)-mediated engements of tumor cells activates FAK which inhibits p53 and its downstream targets including 14-3-3-σ and p21 which promote cellular proliferation and prevent senescence. Overall, these studies suggest that fibrin(ogen) is the important component of the CRC microenvironment and could be exploited for targeting and treating the CRC. Disclosures Whitlock: POSNA: Other: Research Committee; MTF Biologics Grant Program: Other: site co-investigator. Palumbo:Ionis Pharmaceuticals: Research Funding.

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Tabe, Yoko, Yasushi Isobe, Koichi Sugimoto, Linhua Jin, Kazuo Oshimi, and Takashi Miida. "The MDM2 Antagonist Nutlin-3 Is Effective to Aggressive NK-Cell Neoplasms with Wild Type p53 in Hypoxia." Blood 118, no. 21 (November 18, 2011): 4999. http://dx.doi.org/10.1182/blood.v118.21.4999.4999.

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Abstract Abstract 4999 Natural killer (NK) cell neoplasms, including extranodal NK/T-cell lymphoma, nasal type (ENKL) and aggressive NK cell leukemia (ANKL), show a highly aggressive clinical course with poor response to chemotherapy, and new treatment approaches are urgently needed to improve cure rates. Patients with NK cell neoplasms cluster in Asia and Latin American countries, and the frequency of p53 mutations has been reported to be various by district. We have demonstrated that MDM2 protein was overexpressed in aggressive subclasses of NK cell neoplasms (Sugimoto et al. Jap J Cancer Res. 2002), which suggests that wild-type p53 expressing malignant NK cells may be a good candidate for biologic therapies that abrogate MDM2-p53 interactions and lead to cell death. Nutlin-3 is a small-molecule antagonist of MDM2 that efficiently blocks the MDM2-p53 interaction. In this study, we investigated the effects of nutlin-3 in 3 cell lines of ENKL and ANKL with known p53 mutation status (wt-p53: NK-YS, HANK-1; mt-p53: KHYG-1). Since aggressive NK-cell neoplasms arise in hypoxic environments and usually show an angiodestructive-infiltration pattern resulting in the tissue necrosis, we tried to assess the anti-proliferative effects and molecular mechanisms of nutlin-3 in the hypoxic condition. For hypoxia experiments, cells were cultured under 1.0% O2 for at least 14 days to assure their continuous proliferation and survival. Under hypoxia, more cells were positive to Annexin V than in normoxia, indicating that hypoxic conditions promote apoptosis in NK cell neoplasms. Nutlin-3 treatment in normoxia resulted in a reduction of cell proliferation with G0/G1 cell cycle arrest in a time and concentration-dependent manner in wt-p53 cells (IC50 at 48 hrs; 3.2 μM for NK-YS and 5.0 μM for HANK-1, MTT test). In hypoxia, nutlin-3 further enhanced cell growth inhibition and G0/G1 cell cycle arrest. An increase in the specific apoptosis (sub G1 and annexin V positivity) by nutlin-3 was observed with similar level between normoxia and hypoxia. The mt-p53 KHYG-1 cells demonstrated neither cell cycle arrest nor increase in the apoptotic cell fraction after nutlin-3 treatment. In the wt-p53 NK-YS and HANK-1 cells, nutlin-3 treatment increased the cellular levels of p53, and p53 dependent proteins including p21, MDM2 itself and the proapoptotic BH3-only proteins Noxa and Puma followed by the activation of caspase-9 and caspase-3 regardless of foxygen level. We observed no significant increase in the p53 targets in the mt-p53 overexpressing KHYG-1 cells. L-asparaginase has been demonstrated to induce apoptosis in aggressive NK cell neopplasms. To determine if inhibition of the TP53-MDM2 interaction by nutlin-3 in NK cell neoplasms might potentiate the effects of L-asparaginase, we assessed the effect of combining the two drugs. However, L-asparaginase induced apoptosis only in NK-YS cells, and no synergistic anti-proliferative effect was observed in any of the cell lines analyzed. These findings demonstrate that nutlin-3 successfully activates wt-p53 in NK cell neoplasms leading to the upregulation of traditional targets such as p21 and proapoptotic proteins including Noxa and Puma, and result in apoptotic cell death regardless of oxygen concentration. The data suggest that p53 activators such as nutlin-3 may be considerable for selected patients with wt-p53 NK cell neoplasms. Disclosures: No relevant conflicts of interest to declare.

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Narasimhan, Sudha Rani, Lin Yang, Brenda I. Gerwin, and V. Courtney Broaddus. "Resistance of pleural mesothelioma cell lines to apoptosis: relation to expression of Bcl-2 and Bax." American Journal of Physiology-Lung Cellular and Molecular Physiology 275, no. 1 (July 1, 1998): L165—L171. http://dx.doi.org/10.1152/ajplung.1998.275.1.l165.

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A failure of normal apoptosis, often due to mutant p53, may contribute to the formation of a cancer and to its resistance to therapy. Mesothelioma, an asbestos-induced tumor, is highly resistant to therapy but generally expresses wild-type p53. We asked whether mesothelioma was resistant to apoptosis and whether resistance was associated with altered expression of the antiapoptotic protein Bcl-2 or proapoptotic protein Bax. We found that three mesothelioma cell lines (1 with wild-type p53) were highly resistant to apoptosis induced by oxidant stimuli (asbestos, H2O2) or nonoxidant stimuli (calcium ionophore) compared with primary cultured mesothelial cells. By immunostaining, one of these three lines expressed Bcl-2 but only during mitosis. By immunoblotting, 3 of 14 additional mesothelioma lines (9 of 14 with wild type p53) expressed Bcl-2 but all 14 of 14 expressed the proapoptotic Bax, giving a low ratio of Bcl-2 to Bax. We conclude that mesothelioma cell lines are resistant to apoptosis and that the failure in apoptosis is not explained by Bcl-2 but by other mechanisms that counteract the proapoptotic effect of Bax.

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Wu, Shin-Hwar, Tzu-Yun Wu, Yung-Ting Hsiao, Ju-Hwa Lin, Shu-Chun Hsu, Te-Chun Hsia, Su-Tso Yang, Wu-Huei Hsu, and Jing-Gung Chung. "Bufalin Induces Cell Death in Human Lung Cancer Cells through Disruption of DNA Damage Response Pathways." American Journal of Chinese Medicine 42, no. 03 (January 2014): 729–42. http://dx.doi.org/10.1142/s0192415x14500475.

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Bufalin is a key component of a Chinese medicine (Chan Su) and has been proved effective in killing various cancer cells. Its role in inducing DNA damage and the inhibition of the DNA damage response (DDR) has been reported, but none have studied such action in lung cancer in detail. In this study, we demonstrated bufalin-induced DNA damage and condensation in NCI-H460 cells through a comet assay and DAPI staining, respectively. Western blotting indicated that bufalin suppressed the protein levels associated with DNA damage and repair, such as a DNA dependent serine/threonine protein kinase (DNA-PK), DNA repair proteins breast cancer 1, early onset (BRCA1), 14-3-3 σ (an important checkpoint keeper of DDR), mediator of DNA damage checkpoint 1 (MDC1), O6-methylguanine-DNA methyltransferase (MGMT) and p53 (tumor suppressor protein). Bufalin could activate phosphorylated p53 in NCI-H460 cells. DNA damage in NCI-H460 cells after treatment with bufalin up-regulated its ATM and ATR genes, which encode proteins functioning as sensors in DDR, and also up-regulated the gene expression (mRNA) of BRCA1 and DNA-PK. But bufalin suppressed the gene expression (mRNA) of p53 and 14-3-3 σ, however, bufalin did not significantly affect the mRNA of MGMT. In conclusion, bufalin induced DNA damage in NCI-H460 cells and also inhibited its DNA repair and checkpoint function.

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Nunun, Somrudee, Paramee Thongsuksai, Keson Trakunrum та Pritsana Raungrut. "Down-Regulation of 14-3-3σ Reduces Proliferation of Human Lung Cancers But Not Colon Cancer Cells". Journal of Health Science and Medical Research 36, № 2 (24 травня 2018): 97. http://dx.doi.org/10.31584/jhsmr.2018.36.2.3.

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Objective: 14-3-3σ protein is well known for its tumor suppressive function in breast cancer. However, recent evidence has raised the possibility that the 14-3-3σ protein may also have an oncogenic function in certain cancer types. The aim of this study was to investigate the oncogenic function of 14-3-3σ in adenocarcinoma cell lines of the lung (A549, H358) and colon (HT-29).Material and Methods: siRNA against 14-3-3σ was used to suppress 14-3-3σ expression. Cell proliferation, cell-cycle distribution and expression of related molecules were determined by MTT, flow cytometry, and western blotting, respectively.Results: Down-regulation of 14-3-3σ significantly reduced the proliferation of A549 and H358 by 35.0% and 31.0%, respectively, and significantly induced cell cycle arrest at the G0/G1 and G2/M phases, respectively. Increased p21 expression by 43.0% was only observed in si-14-3-3σ-H358 cells. The si-14-3-3σ-HT-29 cells showed no alteration of cell proliferation and cell-cycle distribution but harbored reduced p53 expression by 56.0% and p27 expression by 67.0%.Conclusion: 14-3-3σ may have an oncogenic function in lung adenocarcinoma but play a different role in colon cancer.

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Nunun, Somrudee, Paramee Thongsuksai, Keson Trakunrum та Pritsana Raungrut. "Down-Regulation of 14-3-3σ Reduces Proliferation of Human Lung Cancers But Not Colon Cancer Cells". Journal of Health Science and Medical Research 36, № 2 (24 травня 2018): 97. http://dx.doi.org/10.31584/jhsmr.v36i2.3.

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Objective: 14-3-3σ protein is well known for its tumor suppressive function in breast cancer. However, recent evidence has raised the possibility that the 14-3-3σ protein may also have an oncogenic function in certain cancer types. The aim of this study was to investigate the oncogenic function of 14-3-3σ in adenocarcinoma cell lines of the lung (A549, H358) and colon (HT-29).Material and Methods: siRNA against 14-3-3σ was used to suppress 14-3-3σ expression. Cell proliferation, cell-cycle distribution and expression of related molecules were determined by MTT, flow cytometry, and western blotting, respectively.Results: Down-regulation of 14-3-3σ significantly reduced the proliferation of A549 and H358 by 35.0% and 31.0%, respectively, and significantly induced cell cycle arrest at the G0/G1 and G2/M phases, respectively. Increased p21 expression by 43.0% was only observed in si-14-3-3σ-H358 cells. The si-14-3-3σ-HT-29 cells showed no alteration of cell proliferation and cell-cycle distribution but harbored reduced p53 expression by 56.0% and p27 expression by 67.0%.Conclusion: 14-3-3σ may have an oncogenic function in lung adenocarcinoma but play a different role in colon cancer.

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Huang, Sheng-Yen, Min-Jie Hsieh, Chu-Ying Chen, Yen-Ju Chen, Jen-Yang Chen, Mei-Ru Chen, Ching-Hwa Tsai, Su-Fang Lin та Tsuey-Ying Hsu. "Epstein–Barr virus Rta-mediated transactivation of p21 and 14-3-3σ arrests cells at the G1/S transition by reducing cyclin E/CDK2 activity". Journal of General Virology 93, № 1 (1 січня 2012): 139–49. http://dx.doi.org/10.1099/vir.0.034405-0.

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Many herpesviral immediate-early proteins promote their robust lytic phase replications by hijacking the cell cycle machinery. Previously, lytic replication of Epstein–Barr virus (EBV) was found to be concurrent with host cell cycle arrest. In this study, we showed that ectopic expression of EBV immediate-early protein Rta in HEp-2 cells resulted in increased G1/S population, hypophosphorylation of pRb and decreased incorporation of 5-bromo-2′-deoxyuridine. In addition, EBV Rta transcriptionally upregulates the expressions of p21 and 14-3-3σ in HEp-2 cells, 293 cells and nasopharyngeal carcinoma TW01 cells. Although p21 and 14-3-3σ are known targets for p53, Rta-mediated p21 and 14-3-3σ transactivation can be detected in the absence of p53. In addition, results from luciferase reporter assays indicated that direct binding of Rta to either promoter sequences is not required for activation. On the other hand, a special class of Sp1-responsive elements was involved in Rta-mediated transcriptional activation on both promoters. Finally, Rta-induced p21 expression diminished the activity of CDK2/cyclin E complex, and, Rta-induced 14-3-3σ expression sequestered CDK1 and CDK2 in the cytoplasm. Based on these results, we hypothesize that through the disruption of CDK1 and CDK2 activities, EBV Rta might contribute to cell cycle arrest in EBV-infected epithelial cells during viral reactivation.

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Szkaradkiewicz, Andrzej, Tomasz Karpiński, Jan Majewski, Kamila Malinowska, Olga Goślińska-Kuźniarek, and Krzysztof Linke. "The Participation of p53 and bcl-2 Proteins in Gastric Carcinomas Associated with Helicobacter pylori and/or Epstein-Barr Virus (EBV)." Polish Journal of Microbiology 64, no. 3 (September 18, 2015): 211–16. http://dx.doi.org/10.5604/01.3001.0009.2116.

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In the presented studies p53 and bcl-2 proteins expression were evaluated in samples of gastric carcinomas in patients with Helicobacter pylori or EBV or without H. pylori/EBV infection. The studies were conducted on 64 adult patients with gastric adenocarcinomas: 16 patients with H. pylori (cagA+)-positivity (group 1), 14 with EBV-positive tumours (group 2), 12 with H. pylori/EBV-positive tumours (group 3) and 22 patients with H. pylori/EBV-negative tumours (group 4). H. pylori presence in gastric tumour specimens was detected using Giemsa staining and bacterial culture technique. Moreover, cagA gene was detected using PCR. EBV infection was detected based on EBER presence in the tissue by RNA in situ hybridization. Expressions of p53 and bcl-2 proteins were analysed using immunohistochemistry. Expression of p53 was noted in 14 (84%) patients from group 1, 8 (57%) patients from group 2, 7 (58%) patients from group 3, and 19 (86%) patients from group 4, whereas expression of bcl-2 was noted in 12 (75%) patients from group 1, in 10 (71%) patients from group 2, 9 (75%) patients from group 3, and 6 (27%) patients from group 4. The obtained results allow the conclusion, that H. pylori (cagA+)-associated development of the gastric adenocarcinoma is determined by abnormalities in the p53 protein function and overexpression of anti-apoptotic bcl-2 protein, whereas EBV-associated adenocarcinomas seem to be related with apoptosis resistance associated with bcl-2 overexpression.

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Westfall, Matthew D., Deborah J. Mays, Joseph C. Sniezek та Jennifer A. Pietenpol. "The ΔNp63α Phosphoprotein Binds the p21 and 14-3-3σ Promoters In Vivo and Has Transcriptional Repressor Activity That Is Reduced by Hay-Wells Syndrome-Derived Mutations". Molecular and Cellular Biology 23, № 7 (1 квітня 2003): 2264–76. http://dx.doi.org/10.1128/mcb.23.7.2264-2276.2003.

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ABSTRACT p63 is a recently identified homolog of p53 that is found in the basal layer of several stratified epithelial tissues such as the epidermis, oral mucosa, prostate, and urogenital tract. Studies with p63−/− mice and analysis of several human autosomal-dominant disorders with germ line p63 mutations suggest p63 involvement in maintaining epidermal stem cell populations. The p63 gene encodes six splice variants with reported transactivating or dominant-negative activities. The goals of the current study were to determine the splice variants that are expressed in primary human epidermal keratinocytes (HEKs) and the biochemical activity p63 has in these epithelial cell populations. We found that the predominant splice variant expressed in HEKs was ΔNp63α, and it was present as a phosphorylated protein. During HEK differentiation, ΔNp63α and p53 levels decreased, while expression of p53 target genes p21 and 14-3-3σ increased. ΔNp63α had transcriptional repressor activity in vitro, and this activity was reduced in ΔNp63α proteins containing point mutations, corresponding to those found in patients with Hay-Wells syndrome. Further, we show that ΔNp63α and p53 can bind the p21 and 14-3-3σ promoters in vitro and in vivo, with decreased binding of p63 to these promoters during HEK differentiation. These data suggest that ΔNp63α acts as a transcriptional repressor at select growth regulatory gene promoters in HEKs, and this repression likely plays an important role in the proliferative capacity of basal keratinocytes.

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Li, Honghui, Wenmin Cheng, Bowei Chen, Shaoxia Pu, Ninglin Fan, Xiaolin Zhang, Deling Jiao, et al. "Efficient Generation of P53 Biallelic Mutations in Diannan Miniature Pigs Using RNA-Guided Base Editing." Life 11, no. 12 (December 17, 2021): 1417. http://dx.doi.org/10.3390/life11121417.

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The base editing 3 (BE3) system, a single-base gene editing technology developed using CRISPR/Cas9n, has a broad range of applications for human disease model construction and gene therapy, as it is highly efficient, accurate, and non-destructive. P53 mutations are present in more than 50% of human malignancies. Due to the similarities between humans and pigs at the molecular level, pig models carrying P53 mutations can be used to research the mechanism of tumorigenesis and improve tumor diagnosis and treatment. According to pathogenic mutations of the human P53 gene at W146* and Q100*, sgRNAs were designed to target exon 4 and exon 5 of the porcine P53 gene. The target editing efficiencies of the two sgRNAs were 61.9% and 50.0%, respectively. The editing efficiency of the BE3 system was highest (about 60%) when C (or G) was at the 5th base. Puromycin screening revealed that 75.0% (21/28) and 68.7% (22/32) of cell colonies contained a P53 mutation at sgRNA-Exon5 and sgRNA-Exon4, respectively. The reconstructed embryos from sgRNA-Exon5-5# were transferred into six recipient gilts, all of which aborted. The reconstructed embryos from sgRNA-Exon4-7# were transferred into 6 recipient gilts, 3 of which became pregnant, resulting in 14 live and 3 dead piglets. Sequencing analyses of the target site confirmed 1 P53 monoallelic mutation and 16 biallelic mutations. The qPCR analysis showed that the P53 mRNA expression level was significantly decreased in different tissues of the P53 mutant piglets (p < 0.05). Additionally, confocal microscopy and western blot analysis revealed an absence of P53 expression in the P53 mutant fibroblasts, livers, and lung tissues. In conclusion, a porcine cancer model with a P53 point mutation can be obtained via the BE3 system and somatic cell nuclear transfer (SCNT).

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Martínez-Galán, Joaquina, Cynthia S. González Rivas, Julia Ruiz Vozmediano, Pedro Ballesteros, Juan Ramón Delgado, Sandra Ríos, M. Isabel Núñez, Jesus Lopez-Peñalver, and Blanca Torres-Torres. "Implications prognostics of methylation 14-3-3 sigma promoter in peripheral blood cell DNA with nodal involvement status and tumor size for breast cancer patients." Journal of Clinical Oncology 30, no. 27_suppl (September 20, 2012): 33. http://dx.doi.org/10.1200/jco.2012.30.27_suppl.33.

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33 Background: Expression of 14-3-3 σ is a tumor suppressor gene induced in response to DNA damage, and has been implicated in G2/M cell cycle arrest by p53. Hypermethylation of CpG islands located in the promoter regions of tumor suppressor genes is now firmly established as an important mechanism for gene inactivation. To correlation methylation levels of promoter 14-3-3σ with association prognostic factors in breast cancer. Methods: This is a prospective study we quantified methylation levels of promoter 14-3-3σ gene in 107 women with breast cancer and 108 control subjects by Real Time QMS-PCR SYBR green and analyzed association with prognostics factor in breast cancer. Results: Median age was 58 years (32-88); 69% were postmenopausal women. Nodal involvement N0; 63%,N1;30%,N2;7%), tumor size (T1;58%,T2;35%,T3;4%,T4;4%) and grade G1; 20%,G2;37%,G3;30%). The methylation of 14-3-3σ were 60% of sporadic breast cancer patients and were 34% of normal breast (p=0.0047). The methylation of 14-3-3σ gene in serum was markedly related with T3-4 stage (p<0.05),nodal positive status (p<0.05) and poor outcome. With a median follow up 6 years we saw more probability of developing distance metastasis in patients with methylation 14-3-3σ (p>0.05). Conclusions: Hypermethylation of the 14-3-3σ a promoter is an early and frequent event in breast neoplastic transformation, leading to the suggestion that silencing of 14-3-3σ may be an important event in tumor progression and particularly in breast carcinogenesis.Therefore, it is possible that loss of σ expression contributes to malignant transformation by impairing the G2 cell cycle checkpoint function, thus allowing an accumulation of genetic defects. Perhaps in the detection of CpG methylation of 14-3-3σ may be used for diagnostic and prognostic purposes.

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Maurya, Rajendra Prakash, Sanjay Kumar Bosak, Royana Singh, Virendra Pratap Singh, Samer Singh, Per O. Lundmark, Shivangi Singh, Anil Kumar, and Tanmay Srivastav. "Analysis of tumor protein p53 (p53) mutations in eyelid malignancy." IP International Journal of Ocular Oncology and Oculoplasty 7, no. 3 (October 15, 2021): 243–49. http://dx.doi.org/10.18231/j.ijooo.2021.051.

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The tumor protein p53 (or p53) gene plays a major role in the maintenance of normal cell growth and differentiation. Alteration in p53 gene is responsible for carcinogenesis. In this study, we evaluated the frequency of p53 mutation and clinicopathological findings in various eyelid malignancies. We reviewed a cohort of 20 patients with various eyelid malignancies over one year. The expression of p53protein was analyzed by amplifying the exons 5-9 of p53 gene by conventional Polymerase Chain Reaction (PCR) followed by sequencing to identify mutations. The commonest eyelid malignancies was sebaceous gland carcinoma (SGC;50%) followed by basal cell carcinoma (BCC;45%) and squamous cell carcinoma(SCC; 5%). Study population/patients were mostly elderly (60 %, > 50 years of age) and female (75%). A total of 14 mutations were identified in the p53 genes in 9/20 (45%) patients at different intron or exon. Amongst them 6 patients (66.7%) had SGC and 3 (33.3%) had BCC. Out of the total 14 mutations identified, 8 intronic variation and 6 exonic mutations were identified. Out of 6 exonic variations, 5 caused frame shift mutations due to insertion or deletion of bases and one case was of substitution mutation (D281Y).Sebaceous gland carcinoma (SGC) was found to be most prevalent eyelid cancer in the present study and it most frequent displayed mutation inthe p53 genes among the all eyelid tumors investigated.

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