Relevant bibliographies by topics / PI3K

Academic literature on the topic 'PI3K'

Author: Grafiati
Published: 4 June 2021
Last updated: 8 June 2024

Create a spot-on reference in APA, MLA, Chicago, Harvard, and other styles

Select a source type:

Contents

Consult the lists of relevant articles, books, theses, conference reports, and other scholarly sources on the topic 'PI3K.'

Next to every source in the list of references, there is an 'Add to bibliography' button. Press on it, and we will generate automatically the bibliographic reference to the chosen work in the citation style you need: APA, MLA, Harvard, Chicago, Vancouver, etc.

You can also download the full text of the academic publication as pdf and read online its abstract whenever available in the metadata.

Journal articles on the topic "PI3K"

1

Hus, Iwona, Bartosz Puła, and Tadeusz Robak. "PI3K Inhibitors for the Treatment of Chronic Lymphocytic Leukemia: Current Status and Future Perspectives." Cancers 14, no. 6 (March 18, 2022): 1571. http://dx.doi.org/10.3390/cancers14061571.

Full text
Abstract:
Phosphoinositide 3-kinases (PI3Ks) signaling regulates key cellular processes, such as growth, survival and apoptosis. Among the three classes of PI3K, class I is the most important for the development, differentiation and activation of B and T cells. Four isoforms are distinguished within class I (PI3Kα, PI3Kβ, PI3Kδ and PI3Kγ). PI3Kδ expression is limited mainly to the B cells and their precursors, and blocking PI3K has been found to promote apoptosis of chronic lymphocytic leukemia (CLL) cells. Idelalisib, a selective PI3Kδ inhibitor, was the first-in-class PI3Ki introduced into CLL treatment. It showed efficacy in patients with del(17p)/TP53 mutation, unmutated IGHV status and refractory/relapsed disease. However, its side effects, such as autoimmune-mediated pneumonitis and colitis, infections and skin changes, limited its widespread use. The dual PI3Kδ/γ inhibitor duvelisib is approved for use in CLL patients but with similar toxicities to idelalisib. Umbralisib, a highly selective inhibitor of PI3Kδ and casein kinase-1ε (CK1ε), was found to be efficient and safe in monotherapy and in combination regimens in phase 3 trials in patients with CLL. Novel PI3Kis are under evaluation in early phase clinical trials. In this paper we present the mechanism of action, efficacy and toxicities of PI3Ki approved in the treatment of CLL and developed in clinical trials.
APA, Harvard, Vancouver, ISO, and other styles
2

Bohat, Ritu, Xiaofang Liang, Chunyu Xu, Yitao Tang, Jiakai Hou, Nicholas A. Egan, Leilei Shi, et al. "Abstract 4444: Targeting PI3K isoforms to improve the effectiveness of T cell mediated immunotherapy." Cancer Research 83, no. 7_Supplement (April 4, 2023): 4444. http://dx.doi.org/10.1158/1538-7445.am2023-4444.

Full text
Abstract:
Abstract Hyperactivation of the PI3K pathway has been reported to correlate with resistance to immune checkpoint blockade therapy (ICB) in melanoma, highlighting the therapeutic potential of combining PI3K inhibition (PI3Ki) with ICB. To maximize the clinical benefit of PI3Ki-based immune oncology (IO) combination, we characterized the role of PI3K isoforms in tumor and T cells and determined the immunological impacts of PI3Ki alone or in combination with ICB. Inhibitions of PI3K were achieved by either genetic knockdown (KD) or the bioactive compound in PTEN-present (B16/MC38), PTEN-absent (BP/D4M) tumor cell lines, and CD8+ T cells (Pmel-1). Following PI3Ki, we determined the activation status of the PI3K pathway (p-AKT level), transcriptional profile, and cellular function of these cells. We found both in vitro KD and pharmacological inhibition of either PI3Kα or PI3Kβ displayed a dramatic reduction of the PI3K pathway in tumor cells but moderate or no reduction in T cells, whereas the PI3K pathway significantly decreased in T cells with PI3Kγ or PI3Kδ inhibition. KD of PI3Kα or β isoforms drastically sensitized both D4M and MC38 tumors to αPD1 in vivo. We also observed that only PI3Kγ or PI3Kδ inhibition profoundly suppressed cytokine production and cytotoxicity of CD8+ T cell, suggesting that PI3Kα or PI3Kβ isoform inhibition can achieve tumor specific PI3Ki with limited impacts on T cell function. Furthermore, we used multiple syngeneic melanoma models to determine whether PI3K isoform inhibition can synergize the antitumor activity of ICB in vivo. In PTEN-present tumors, BYL719 (BYL, a PI3Kα inhibitor) synergized with αPD1 to delay tumor growth and extend survival (median survival of MC38-bearing mice in control (Ctrl), BYL, αPD1, and combination (Comb) groups: 30, 36, 33, and >45 respectively; p<0.05: Ctrl/BYL/αPD1 vs Comb). However, a limited combinatorial effect between GSK2636771(a PI3Kβ inhibitor) and αPD1 was observed in PTEN-present tumor models. Moreover, the combination of BYL and αPD1 exhibits superior antitumor activity in a spontaneous Braf-mutant, PTEN-loss melanoma model when compared with either reagent. Mechanistically, the combination of BYL and αPD1 improved CD8+ T cells tumor infiltration (14 days treatment, mean CD8+ number/mg of the tumor, Ctrl:1392.9, BYL:2073.9, αPD1:1545.2, Comb:4691.8; p<0.01: Ctrl/BYL/αPD1 vs Comb) and reduced MDSCs in MC38 tumors (p<0.05: Ctrl vs Comb). Multi-omics profiling of tumor cells with in vitro and in vivo PI3K isoform inhibition is ongoing. Collectively, our results demonstrate that PI3Kα inhibitor can potentiate T cell-mediated antitumor immune responses regardless of PTEN status, providing a strong rationale for the clinical development of the BYL-based IO combination. In collaboration with Novartis, MD Anderson Cancer Center will launch a Phase I/II trial of the FDA-approved BYL in combination with αPD1 in advanced melanoma and breast cancer patients. Citation Format: Ritu Bohat, Xiaofang Liang, Chunyu Xu, Yitao Tang, Jiakai Hou, Nicholas A. Egan, Leilei Shi, Ashley Guerrero, Roshni Jaffery, Elizabeth M. Burton, Han Liang, Hussein Tawbi, Michael A. Davies, Weiyi Peng. Targeting PI3K isoforms to improve the effectiveness of T cell mediated immunotherapy. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4444.
APA, Harvard, Vancouver, ISO, and other styles
3

Miller, Michelle, Philip Thompson, and Sandra Gabelli. "Structural Determinants of Isoform Selectivity in PI3K Inhibitors." Biomolecules 9, no. 3 (February 26, 2019): 82. http://dx.doi.org/10.3390/biom9030082.

Full text
Abstract:
Phosphatidylinositol 3-kinases (PI3Ks) are important therapeutic targets for the treatment of cancer, thrombosis, and inflammatory and immune diseases. The four highly homologous Class I isoforms, PI3Kα, PI3Kβ, PI3Kγ and PI3Kδ have unique, non-redundant physiological roles and as such, isoform selectivity has been a key consideration driving inhibitor design and development. In this review, we discuss the structural biology of PI3Ks and how our growing knowledge of structure has influenced the medicinal chemistry of PI3K inhibitors. We present an analysis of the available structure-selectivity-activity relationship data to highlight key insights into how the various regions of the PI3K binding site influence isoform selectivity. The picture that emerges is one that is far from simple and emphasizes the complex nature of protein-inhibitor binding, involving protein flexibility, energetics, water networks and interactions with non-conserved residues.
APA, Harvard, Vancouver, ISO, and other styles
4

Hawkins, P. T., K. E. Anderson, K. Davidson, and L. R. Stephens. "Signalling through Class I PI3Ks in mammalian cells." Biochemical Society Transactions 34, no. 5 (October 1, 2006): 647–62. http://dx.doi.org/10.1042/bst0340647.

Full text
Abstract:
It is now accepted that activation of Class I PI3Ks (phosphoinositide 3-kinases) is one of the most important signal transduction pathways used by cell-surface receptors to control intracellular events. The receptors which access this pathway include those that recognize growth factors, hormones, antigens and inflammatory stimuli, and the cellular events known to be regulated include cell growth, survival, proliferation and movement. We have learnt a great deal about the family of Class I PI3K enzymes themselves and the structural adaptations which allow a variety of cell-surface receptors to regulate their activity. Class I PI3Ks synthesize the phospholipid PtdIns(3,4,5)P3 in the membranes in which they are activated, and it is now accepted that PtdIns(3,4,5)P3 and its dephosphorylation product PtdIns(3,4)P2 are messenger molecules which regulate the localization and function of multiple effectors by binding to their specific PH (pleckstrin homology) domains. The number of direct PtdIns(3,4,5)P3/PtdIns(3,4)P2 effectors which exist, even within a single cell, creates an extremely complex signalling web downstream of PI3K activation. Some key players are beginning to emerge, however, linking PI3K activity to specific cellular responses. These include small GTPases for the Rho and Arf families which regulate the cytoskeletal and membrane rearrangements required for cell movement, and PKB (protein kinase B), which has important regulatory inputs into the regulation of cell-cycle progression and survival. The importance of the PI3K signalling pathway in regulating the balance of decisions in cell growth, proliferation and survival is clear from the prevalence of oncogenes (e.g. PI3Kα) and tumour suppressors [e.g. the PtdIns(3,4,5)P3 3-phosphatase, PTEN (phosphatase and tensin homologue deleted on chromosome 10)] found in this pathway. The recent availability of transgenic mouse models with engineered defects in Class I PI3K signalling pathways, and the development of PI3K isoform-selective inhibitors by both academic and pharmaceutical research has highlighted the importance of specific isoforms of PI3K in whole-animal physiology and pathology, e.g. PI3Kα in growth and metabolic regulation, PI3Kβ in thrombosis, and PI3Kδ and PI3Kγ in inflammation and asthma. Thus the Class I PI3K signalling pathway is emerging as an exciting new area for the development of novel therapeutics.
APA, Harvard, Vancouver, ISO, and other styles
5

Garcia, Analia, Soochong Kim, Kamala Bhavaraju, Simone M. Schoenwaelder, and Satya P. Kunapuli. "Role of phosphoinositide 3-kinase β in platelet aggregation and thromboxane A2 generation mediated by Gi signalling pathways." Biochemical Journal 429, no. 2 (June 28, 2010): 369–77. http://dx.doi.org/10.1042/bj20100166.

Full text
Abstract:
PI3Ks (phosphoinositide 3-kinases) play a critical role in platelet functional responses. PI3Ks are activated upon P2Y12 receptor stimulation and generate pro-aggregatory signals. P2Y12 receptor has been shown to play a key role in the platelet aggregation and thromboxane A2 generation caused by co-stimulation with Gq or Gz, or super-stimulation of Gi pathways. In the present study, we evaluated the role of specific PI3K isoforms α, β, γ and δ in platelet aggregation, thromboxane A2 generation and ERK (extracellular-signal-regulated kinase) activation. Our results show that loss of the PI3K signal impaired the ability of ADP to induce platelet aggregation, ERK phosphorylation and thromboxane A2 generation. We also show that Gq plus Gi- or Gi plus Gz-mediated platelet aggregation, ERK phosphorylation and thromboxane A2 generation in human platelets was inhibited by TGX-221, a PI3Kβ-selective inhibitor, but not by PIK75 (a PI3Kα inhibitor), AS252424 (a PI3Kγ inhibitor) or IC87114 (a PI3Kδ inhibitor). TGX-221 also showed a similar inhibitory effect on the Gi plus Gz-mediated platelet responses in platelets from P2Y1−/− mice. Finally, 2MeSADP (2-methyl-thio-ADP)-induced Akt phosphorylation was significantly inhibited in the presence of TGX-221, suggesting a critical role for PI3Kβ in Gi-mediated signalling. Taken together, our results demonstrate that PI3Kβ plays an important role in ADP-induced platelet aggregation. Moreover, PI3Kβ mediates ADP-induced thromboxane A2 generation by regulating ERK phosphorylation.
APA, Harvard, Vancouver, ISO, and other styles
6

Stypik, Mariola, Stanisław Michałek, Nina Orłowska, Marcin Zagozda, Maciej Dziachan, Martyna Banach, Paweł Turowski, et al. "Design, Synthesis, and Development of Pyrazolo[1,5-a]pyrimidine Derivatives as a Novel Series of Selective PI3Kδ Inhibitors: Part II—Benzimidazole Derivatives." Pharmaceuticals 15, no. 8 (July 27, 2022): 927. http://dx.doi.org/10.3390/ph15080927.

Full text
Abstract:
Phosphoinositide 3-kinase (PI3K) is the family of lipid kinases participating in vital cellular processes such as cell proliferation, growth, migration, or cytokines production. Due to the high expression of these proteins in many human cells and their involvement in metabolism regulation, normal embryogenesis, or maintaining glucose homeostasis, the inhibition of PI3K (especially the first class which contains four subunits: α, β, γ, δ) is considered to be a promising therapeutic strategy for the treatment of inflammatory and autoimmune diseases such as systemic lupus erythematosus (SLE) or multiple sclerosis. In this work, we synthesized a library of benzimidazole derivatives of pyrazolo[1,5-a]pyrimidine representing a collection of new, potent, active, and selective inhibitors of PI3Kδ, displaying IC50 values ranging from 1.892 to 0.018 μM. Among all compounds obtained, CPL302415 (6) showed the highest activity (IC50 value of 18 nM for PI3Kδ), good selectivity (for PI3Kδ relative to other PI3K isoforms: PI3Kα/δ = 79; PI3Kβ/δ = 1415; PI3Kγ/δ = 939), and promising physicochemical properties. As a lead compound synthesized on a relatively large scale, this structure is considered a potential future candidate for clinical trials in SLE treatment.
APA, Harvard, Vancouver, ISO, and other styles
7

Diacovo, Thomas, Dosh Whye, Evgeni Efimenko, Jianchung Chen, Valeria Tosello, Kim De Keersmaecker, Adam Kashishian, et al. "Therapeutic Utility of PI3Kγ Inhibition in Leukemogenesis and Tumor Cell Survival." Blood 120, no. 21 (November 16, 2012): 1492. http://dx.doi.org/10.1182/blood.v120.21.1492.1492.

Full text
Abstract:
Abstract Abstract 1492 Aberrant activation of the PI3K/Akt signaling pathway is a frequent event in cancer including various types of leukemia. Consequently, much emphasis has been placed on developing inhibitors that target this pathway. However, this would require an in depth knowledge of the role that specific class I PI3K isoforms (α, β, γ, δ)play in the pathogenesis of a particular hematological malignancy. For instance, PI3Kδ has been shown to be essential for the growth and survival of tumors derived from B cells such as chronic lymphocytic leukemia (CLL). Such knowledge has lead to development of the selective inhibitor GS-1101 (CAL-101) that has shown significant efficacy in clinical trials. Although PI3Kγ plays an important role in modulating the immune function of T cells, its role in leukemogenesis and tumor cell survival is poorly defined. Thus, it is unclear whether an inhibitor that also targets PI3Kγ would be of any benefit in hematological malignancies. T cell acute lymphoblastic leukemia (T-ALL) is an aggressive cancer resulting from clonal proliferation of T lymphoid precursors. Previous reports suggest that hyperactivation of the PI3K/Akt signaling pathway is a common feature of this disease with the majority of cases due to the loss of function of the tumor suppressor PTEN. However, it remains to be determined whether any particular class I PI3K isoform predominates in T-ALL pathogenesis. We now report that in the absence of PTEN-mediated regulation in T cell progenitors that PI3Kγ can promote leukemogenesis even in the absence of its delta counterpart. However, inactivation of both isoforms was necessary for the suppression of tumor development in animals (< 20% dead at 220 days as compare to >85% for controls), suggesting that PI3Kα and/or PI3Kβ cannot adequately compensate for a deficiency in their γ/δ counterparts. The importance of PI3Kγ in tumor progression was established by the inability of the PI3Kδ selective inhibitor IC87114 to reduce tumor burden in mice (Fig. 1A). In contrast, treatment of PI3Kγ deficient tumors with the same inhibitor dramatically reduced disease in affected tissues (Fig. 1B). Based on these observations we developed an inhibitor, designated CAL-130, which targets both PI3Kγ and PI3Kδ in an attempt to exploit the addiction of PTEN null T-ALL tumors to both isoforms. IC50 values of this compound were 1.3 nM and 6.1 nM for p110δ and p110γ catalytic domains, respectively, as compared to 115 nM and 56 nM for p110α and p110β. Importantly, this small molecule does not inhibit additional intracellular signaling pathways (>300 kinases tested) that are critical for general cell function and survival. Oral administration of this compound to diseased mice (blast counts > 50 million/ml) for 7 days reduced tumor burden and extended median survival of treated animals to 45 day as compared 7.5 days for the control group (P<0.001). Of note, this inhibitor did not perturb plasma insulin or glucose levels in contrast to the metabolic perturbations associated with tissue-specific deficiencies in PI3Kα and PI3Kβ. The efficacy of this dual inhibitor was not limited to murine tumors as dual inhibition of PI3Kγ and PI3Kδ in primary human T-ALL cells displaying hyperactivation of this signaling pathway also reduced tumor cell survival by promoting activation of pro-apoptotic pathways. This work advances our understanding of the role that distinct PI3K isoforms play in development and survival of T-ALL and suggest that it may be possible to therapeutically exploit the addiction of this hematological malignancy to PI3Kγ and PI3Kδ. Moreover, by selectively targeting a signaling pathway key to tumor survival, it may be possible to limit toxicities associated with conventional chemotherapeutic agents that broadly affect metabolic pathways and DNA replication. Current studies are focused on evaluating the synergistic effect of PI3Kγ/δ blockade in combination with conventional chemotherapeutic agents used in the treatment of T-ALL. Disclosures: Kashishian: Gilead Sciences: Employment. Lannutti:Gilead Sciences Inc: Employment.
APA, Harvard, Vancouver, ISO, and other styles
8

Huang, Yi Elaine, Miho Iijima, Carole A. Parent, Satoru Funamoto, Richard A. Firtel, and Peter Devreotes. "Receptor-mediated Regulation of PI3Ks Confines PI(3,4,5)P3 to the Leading Edge of Chemotaxing Cells." Molecular Biology of the Cell 14, no. 5 (May 2003): 1913–22. http://dx.doi.org/10.1091/mbc.e02-10-0703.

Full text
Abstract:
Recent studies have demonstrated that PH domains specific for PI(3,4,5)P3 accumulate at the leading edge of a number of migrating cells and that PI3Ks and PTEN associate with the membrane at the front and back, respectively, of chemotaxing Dictyostelium discoideum cells. However, the dependence of chemoattractant induced changes in PI(3,4,5)P3 on PI3K and PTEN activities have not been defined. We find that bulk PI(3,4,5)P3 levels increase transiently upon chemoattractant stimulation, and the changes are greater and more prolonged in pten– cells. PI3K activation increases within 5 s of chemoattractant addition and then declines to a low level of activity identically in wild-type and pten– cells. Reconstitution of the PI3K activation profile can be achieved by mixing membranes from stimulated pi3k1–/pi3k2– cells with cytosolic PI3Ks from unstimulated cells. These studies show that significant control of chemotaxis occurs upstream of the PI3Ks and that regulation of the PI3Ks and PTEN cooperate to shape the temporal and spatial localization of PI(3,4,5)P3.
APA, Harvard, Vancouver, ISO, and other styles
9

Lin, Shu, Zuwen Zhou, Rui Tan, Hua Xu, Huajie Zhang, Weipeng Zhang, Ling Chen, et al. "Abstract 5453: FCN-289, a novel, potent and selective PI3Kδ inhibitor for the treatment of B-cell malignancies." Cancer Research 82, no. 12_Supplement (June 15, 2022): 5453. http://dx.doi.org/10.1158/1538-7445.am2022-5453.

Full text
Abstract:
Abstract Phosphoinositide 3-kinase (PI3K)/AKT/mTOR pathway plays critical roles in cell growth, differentiation, motility, survival, and intracellular trafficking, and is one of the most frequently dysregulated pathways in human cancers including B-cell malignancies. There are 3 classes of PI3K, among which Class I PI3Ks including PI3Kα, β, γ, and δ isoforms are the mostly studied and plays key roles in physiological functions. PI3Kα has a role in insulin-dependent signaling, PI3Kβ functions in platelet aggregation, thrombosis and insulin signaling, and PI3Kγ/δ are expressed mainly in leukocytes and regulate lymphocyte activation, mast cell degranulation, and chemotaxis. Early PI3K inhibitors such as idelalisib are effective against B-cell malignancies such as chronic lymphocytic leukemia, but their clinical use is largely limited due to intolerable toxicities. More selective PI3Kδ inhibitors such as umbralisib (TGR-1202) demonstrates improved clinical efficacy and safety profile compared to current standard of care and was recently approved as a monotherapy for follicular lymphoma and marginal zone lymphoma. However, there is still unmet medical need for novel PI3Kδ inhibitors with improved safety profile and better efficacy to be used as monotherapy and in suitable combination strategies. Here we introduce FCN-289, a novel and oral next-generation PI3Kδ inhibitor. FCN-289 demonstrates potent kinase activity against PI3Kδ with single-digit nanomolar IC50 and remarkably improved selectivity over other PI3K isoforms compared with TGR-1202. FCN-289 exhibits significant anti-proliferating activity against various human diffuse large B-cell lymphoma (DLBCL)-derived cancer cell lines (OCI-LY10, TMD-8 and WSU-NHL) with superior activity compared with TGR-1202. Consistently, FCN-289 shows dose-dependent anti-tumor growth activity superior to that of TGR-1202 at the same and higher dose in TMD-8 DLBCL xenograft models. FCN-289 shows significantly improved anti-tumor activity when combined with BTK inhibitor ibrutinib in TMD-8 and OCI-LY10 DLBCL xenograft models. In non-clinical settings, FCN-289 exhibits good pharmacokinetic (PK) and safety properties with shorter Tmax and higher bioavailability in both rats and dogs, higher exposure in rats, improved CYP450 inhibition profile, and less plasma protein bound ratio compared with TGR-1202.Together, FCN-289 is a novel PI3Kδ inhibitor that possesses more potent in vitro and in vivo anti-cancer activities in B-cell malignancies-derived models with improved selectivity against other PI3K isoforms compared with TGR-1202. Combination with ibrutinib further improves anti-tumor activity compared with monotherapy. FCN-289 shows favorable PK and safety profiles compared with TGR-1202. Our findings highlight the therapeutic potential of FCN-289 as a novel targeted approach as monotherapy or in combination for treating B-cell malignancies. Citation Format: Shu Lin, Zuwen Zhou, Rui Tan, Hua Xu, Huajie Zhang, Weipeng Zhang, Ling Chen, Lijun Yang, Xingdong Zhao, Yanxin Liu, Zongyao Zou, Yuwei Gao, Jiashu Zhou, Weibo Wang. FCN-289, a novel, potent and selective PI3Kδ inhibitor for the treatment of B-cell malignancies [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 5453.
APA, Harvard, Vancouver, ISO, and other styles
10

Tsolakos, N., T. N. Durrant, T. Chessa, S. M. Suire, D. Oxley, S. Kulkarni, J. Downward, et al. "Quantitation of class IA PI3Ks in mice reveals p110-free-p85s and isoform-selective subunit associations and recruitment to receptors." Proceedings of the National Academy of Sciences 115, no. 48 (November 15, 2018): 12176–81. http://dx.doi.org/10.1073/pnas.1803446115.

Full text
Abstract:
Class IA PI3Ks have many roles in health and disease. The rules that govern intersubunit and receptor associations, however, remain unclear. We engineered mouse lines in which individual endogenous class IA PI3K subunits were C-terminally tagged with 17aa that could be biotinylated in vivo. Using these tools we quantified PI3K subunits in streptavidin or PDGFR pull-downs and cell lysates. This revealed that p85α and β bound equivalently to p110α or p110β but p85α bound preferentially to p110δ. p85s were found in molar-excess over p110s in a number of contexts including MEFs (p85β, 20%) and liver (p85α, 30%). In serum-starved MEFs, p110-free-p85s were preferentially, compared with heterodimeric p85s, bound to PDGFRs, consistent with in vitro assays that demonstrated they bound PDGFR-based tyrosine-phosphorylated peptides with higher affinity and co-operativity; suggesting they may act to tune a PI3K activation threshold. p110α-heterodimers were recruited 5–6× more efficiently than p110β-heterodimers to activated PDGFRs in MEFs or to PDGFR-based tyrosine-phosphorylated peptides in MEF-lysates. This suggests that PI3Kα has a higher affinity for relevant tyrosine-phosphorylated motifs than PI3Kβ. Nevertheless, PI3Kβ contributes substantially to acute PDGF-stimulation of PIP3 and PKB in MEFs because it is synergistically, and possibly sequentially, activated by receptor-recruitment and small GTPases (Rac/CDC42) via its RBD, whereas parallel activation of PI3Kα is independent of its RBD. These results begin to provide molecular clarity to the rules of engagement between class IA PI3K subunits in vivo and past work describing “excess p85,” p85α as a tumor suppressor, and differential receptor activation of PI3Kα and PI3Kβ.
APA, Harvard, Vancouver, ISO, and other styles
More sources

Dissertations / Theses on the topic "PI3K"

1

Balakrishnan, Sanjeevi. "Establishing a biological role for class II phosphoinositide 3-kinase (PI3K) enzyme PI3K-C2??" Thesis, Imperial College London, 2012. http://hdl.handle.net/10044/1/39135.

Full text
Abstract:
Phosphoinositide 3-Kinase (PI3K) enzymes control a variety of cellular processes and their deregulation has been extensively investigated in disease conditions including renal disease, autoimmunity and chronic inflammation. Whilst PI3K enzymes have been the subject of intense research activity, the precise biological role of PI3K-C2?? enzyme remains unclear. PI3K-C2??-/- mice developed focal segmental glomerulosclerosis, damaging podocyte morphology and affecting function. My thesis explored the contribution of the PI3K-C2?? enzyme in the pathology of chronic diseases. PI3K-C2??flx/+ mice were mated with ??-actin cre mice, and the resulting F1 progeny, PI3K-C2??flx/- mice were backcrossed to produce PI3K-C2??-/- mice. Analysis of PI3K-C2??-/- mice revealed slightly elevated proteinuria and mild hyperglycaemia. Histological examination of their kidneys showed an increase in glomerular volume, intraglomerular nuclei, mesangial matrix expansion and an infiltration of T cell subsets in the glomeruli compared to control mice. In vitro, mesangial cells derived from PI3K-C2??-/- mice proliferated twice as fast as mesangial cells from control animals, without any stimulus. PI3K-C2??-/- mice exhibited an increase in the levels of leukocytes and displayed augmented proliferation, in presence of mitogenic stimuli. Wild type (WT) mice mesangial cells cultured in PI3K-C2??-/- mice splenocyte conditioned medium, exhibited a dose dependent increase in their proliferation. Induction of glomerulonephritis (GN) using a sub-nephritogenic dose of nephrotoxic serum (NTS) in PI3K-C2??-/- mice, resulted in impaired renal function and aggravated renal tissue damage. PI3K-C2??-/- mice had a greater influx of T cells and macrophages in the diseased glomeruli, but also of activated macrophage functions compared to WT mice. During GN, PI3K-C2??-/- mice developed splenomegaly leading to extramedullary haematopoiesis and increased splenocyte proliferation. PI3K-C2??-/- mice may mediate GN by polarising their cytokine effects via a Th1 pathway. PI3K-C2??-/- mice exhibit a delay in the repair of dermal injury during cutaneous wound healing. PI3K-C2??-/- mice recruit fewer macrophages to the wound site which affects re-epithelialisation, myofibroblast differentiation, angiogenesis and fibroblast mediated remodelling. Delayed wound healing in PI3K-C2??-/- mice might be a consequence of the failure to upregulate pro-inflammatory cytokines at the wound site, which are potential modulators for the recruitment of various cell types to the wound site to accelerate the healing process. To complement these in vivo studies, biochemical analysis on the putative Ras binding domain present in PI3K-C2?? and PI3K-C2?? enzymes was performed by expressing as recombinant proteins. The binding ability of the recombinant proteins to Ras family GTPases was tested. Although this approach initially proved unsuccessful, two putative binding partners, eEF1?? and eEF1?? were identified and have been shown to immunoprecipitate with full length enzymes. My data is the first study to demonstrate a role for the intracellular signalling enzyme, PI3K-C2?? in pathological conditions involving chronic inflammation. Agonist mediated activation of PI3K-C2?? enzyme might serve as a potential therapeutic target to treat chronic diseases.
APA, Harvard, Vancouver, ISO, and other styles
2

Hale, Benjamin G. "Influenza A viruses and PI3K signalling." Thesis, University of St Andrews, 2007. http://hdl.handle.net/10023/483.

Full text
Abstract:
The influenza A virus non-structural (NS1) protein is multifunctional, and during virus-infection NS1 interacts with several factors in order to manipulate host-cell processes. This study reports that NS1 binds directly to p85β, a regulatory subunit of phosphoinositide 3-kinase (PI3K), but not to the related p85α. Expression of NS1 was sufficient to activate PI3K and cause the phosphorylation of a downstream mediator of PI3K signalling, Akt. However, in virus-infected MDCK cells, the kinetics of Akt phosphorylation did not correlate with NS1 expression, and suggested that negative regulation of this signalling pathway occurs subsequent to ~8h post-infection. Mapping studies showed that the NS1:p85β interaction is primarily mediated by the NS1 C-terminal domain and the p85β inter-SH2 (Src homology 2) domain. Additionally, the highly conserved tyrosine at residue 89 (Y89) of NS1 was found to be important for binding and activating PI3K in a phosphorylation-independent manner. The inter-SH2 domain of p85β is a coiled-coil structure that acts as a scaffold for the p110 catalytic subunit of PI3K. As NS1 does not displace p110 from the inter-SH2 domain, a model is proposed whereby NS1 forms an active heterotrimeric complex with PI3K, and disrupts the ability of p85β to control p110 function. Biological studies revealed that a mutant influenza A virus (Udorn/72) expressing NS1 with phenylalanine substituted for tyrosine-89 (Y89F) exhibited a small-plaque phenotype, and grew more slowly in MDCK cells than wild-type virus. Unexpectedly, another mutant influenza A virus strain (WSN/33) expressing NS1-Y89F was not attenuated in MDCK cells, yet appeared to be less pathogenic than wild-type in vivo. Overall, these data indicate a role for NS1-mediated PI3K activation in efficient influenza A virus replication. The potential application of this work to the design of novel anti-influenza drugs and vaccine production is discussed.
APA, Harvard, Vancouver, ISO, and other styles
3

Hale, Benjamin G. "Influenza A viruses and PI3K signalling /." St Andrews, 2008. http://hdl.handle.net/10023/483.

Full text
APA, Harvard, Vancouver, ISO, and other styles
4

White, Angela R. "Shared PI3K signaling abnormalities in brain tumors and epilepsy: PI3K inhibition in PTEN-deficient disorders of the brain." University of Cincinnati / OhioLINK, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1603712831970142.

Full text
APA, Harvard, Vancouver, ISO, and other styles
5

Castel, Morales Pau. "Molecular mechanisms of resistance to PI3K inhibitors." Doctoral thesis, Universitat de Barcelona, 2016. http://hdl.handle.net/10803/396640.

Full text
Abstract:
The development of high-throughput sequencing technologies has prompted the evaluation of large cohorts of different tumor types. The results from these comprehensive genomic studies have revealed the most commonly mutated genes across human cancers, providing further understanding of the pathogenesis, molecular classification, and therapeutic strategies for this disease. PIK3CA, the gene encoding the PI3Kα isoform, is among the most frequently mutated genes in breast, head and neck, colorectal, and lung cancer, among others. Activating mutations in PIK3CA promote hyperactivation of the PI3K/AKT pathway, leading to increased proliferation, cell growth, survival, and metabolism. Current efforts are aimed to develop PI3K inhibitors as an effective therapy for PIK3CA mutated cancers and, despite promising clinical responses, the emergence of drug resistance is a clear limitation. In this doctoral thesis, we have explored these mechanisms of resistance in order to provide a better understanding of tumor evolution upon therapy, define subpopulations of patients that are likely to respond to PI3K inhibitors, and provide novel pharmacological combinations to overcome therapy refractoriness. The loss of the tumor suppressor PTEN was found to play an important role in the resistance of PI3Kα inhibitors in preclinical models and patients, mainly by reactivating the PI3K/AKT pathway as a result of an increased dependency on the PI3Kβ isoform. Our work also demonstrated the notion of tumor evolution and phenotypic convergent evolution in response to therapeutic pressure. Moreover, we have established that intrinsic resistance to PI3Kα inhibitors occurs as a result of incomplete inhibition of the mammalian target of rapamycin complex 1 (mTORC1), a downstream effector of the PI3K/AKT pathway. PI3Kα inhibitor-resistant cells could be re-sensitized through the blockade of phosphoinositide-dependent kinase (PDK1), a constitutively active kinase, using genetic or pharmacologic inhibition. Further experiments showed that the downstream effector of PDK1 is the serum and glucocorticoid-induced kinase 1 (SGK1), which promotes cell survival through the phosphorylation of key proteins such as FOXO3 and TSC2. Accordingly, the resistant phenotype could be also reverted by inhibiting SGK1, a novel pharmacological approach that has revealed interesting roles of this kinase in tumor biology. Genetically engineered mouse models represent reliable tools for investigating the etiology, biology, and progression of human diseases, as well as for exploring novel therapeutic approaches. By serendipity, we discovered the role of PIK3CA mutations in the genesis of venous malformations, an aberration of normal venous development that currently lacks effective treatments. Our mouse models recapitulated the histopathologic features of the disease and provided an experimental platform to test novel pharmacological approaches. PI3Kα inhibitors were effective at reducing the morbidity and mortality of mice carrying venous malformations. The results from this thesis highlight the importance of defining the molecular determinants of sensitivity and resistance to PI3K inhibitors, a therapy that will most likely benefit PIK3CA mutant patients.
El desenvolupament de noves tècniques de seqüenciació massiva ha fomentat l’estudi d’un gran nombre de mostres de diversos tipus tumorals. Els resultats d’aquests estudis genòmics exhaustius ha revelat els gens que es troben mutats en major prevalença, contribuint a una millor comprensió dels processos de patogènesis, classificació molecular i estratègies terapèutiques per a aquesta malaltia. PIK3CA, el gen que codifica per a la isoforma PI3Kα, es troba entre els gens mes freqüentment mutats en el carcinoma de mama, cap i coll, colorectal, pulmó, entre d’altres. Les mutacions activadores a PIK3CA promouen la hiperactivació de la via de senyalització de PI3K/AKT, donant lloc a un increment en la proliferació, la supervivència, i el metabolisme de les cèl·lules tumorals. Els esforços actuals es centren en el desenvolupament d’inhibidors de l’enzim PI3K com a una possible teràpia efectiva en tumors que presenten mutacions a PIK3CA. Tot i que els assajos clínics inicials son prometedors, l’emergència de resistència a aquestes teràpies és una clara limitació. En aquesta tesis doctoral s’han explorat els possibles mecanismes de resistència per intentar entendre com els tumors evolucionen enfront d’aquest fàrmacs, poder definir les subpoblacions de pacients que respondran als inhibidors de PI3K i proporcionar noves combinacions farmacològiques per combatre el fenomen de la resistència. Hem demostrat que la pèrdua del supressor tumoral PTEN juga un paper important en la resistència als inhibidors de PI3Kα, tant en models preclínics com en pacients, mitjançant la reactivació de la via de PI3K/AKT que és resultat d’un increment en la dependència de la isoforma PI3Kβ. El nostre treball també ha evidenciat la noció d’evolució tumoral i ha demostrat el concepte d’evolució convergent fenotípica en resposta a la pressió terapèutica. També s’ha demostrat que la resistència intrínseca als inhibidors de PI3Kα es pot donar com a resultat d’una inhibició incompleta del complex 1 de mTOR (mTORC1), un efector clau de la via de PI3K/AKT. Cèl·lules resistents a inhibidors de PI3Kα es van poder sensibilitzar amb el bloqueig genètic o farmacològic de PDK1, una quinasa constitutivament activa. Experiments addicionals van poder demostrar que l’efector molecular de PDK1 era la quinasa SGK1, la qual promou la supervivència cel·lular a través de la fosforilació de proteïnes clau com FOXO3 i TSC2. El fenotip resistent es va poder revertir mitjançant la inhibició farmacològica d’aquesta proteïna, una aproximació terapèutica que ha revelat un rol interessant en la biologia tumoral. Els models murins modificats genèticament representen una eina segura per a l’estudi de la etiologia, biologia i progressió de malalties humanes, així com per explorar noves aproximacions terapèutiques. Com a resultat d’un descobriment imprevist, també hem pogut revelar el rol de les mutacions de PIK3CA en la formació de malformacions venoses, una aberració del desenvolupament normal de les venes que actualment no tenen un tractament específic. El nostre model animal de malformació venosa recapitula les característiques histopatològigues de la malaltia i proporciona una plataforma experimental única per a l’estudi de noves teràpies. En aquests models animals, els inhibidors de PI3Kα han demostrat ser efectius en la reducció de la morbiditat de les malformacions venoses.
APA, Harvard, Vancouver, ISO, and other styles
6

Figueiredo, Ana Raquel Martins. "Role of PI3K in pericytes during angiogenesis." Doctoral thesis, Universitat de Barcelona, 2017. http://hdl.handle.net/10803/404276.

Full text
Abstract:
Pericytes (PCs) are important regulators of the vascular development promoting vessel growth and stabilization. They have recently emerged as a therapeutic target to promote or inhibit angiogenesis. Therefore, advancing our basic understanding on PCs biology and its molecular regulators during physiological angiogenesis is essential to develop PC-related therapies. One of the major pathways leading to cellular proliferation, migration, and survival is relayed by PI3K. Data from our laboratory and others have demonstrated isoform selectivity stimulating PI3K signalling in the regulation of both, the ECs and vSMCs. Interestingly, in these two cell populations’ p110α seems to be the major isoform. By using pharmacological and genetic tools together with cultured PCs and retinal systems we have found that PCs pass through different states during vessel development, and that PI3K signalling regulates these cells in an isoform-specific manner. We have seen that immature and active PCs promote vessel growth while, mature and quiescent PCs result in vascular stabilization and remodelling. Moreover and unexpectedly, our results have identified p110β as the key regulator of PCs proliferation and growth. Inactivation of p110β in PCs, but not p110α, results in PC proliferation arrest and in several morphological changes, which resemble a more mature PC. Lack of p110β in PCs also leads to a more mature vascular plexus. We observed reduced vessel density, EC proliferation arrest and increased deposition of collagen IV. Furthermore, PTEN seems to be the regulator of PI3K in PCs, opposing the p110β effects and, leading to a more mature and stable PC and subsequently also more mature vasculature. Since p110β-PI3K controls PC growth and proliferation, it suggests that target therapy directed to p110β in cancer could affect PCs. Using a pancreatic neuroendocrine tumour mouse model (RIP1-Tag2) we have seen that pharmacological inhibition of p110β impacts on tumour progression and in PCs growth. However, it also results in a slight reduction in the overall survival of the animal, without affecting their metastatic potential. Therefore, other studies are needed to further investigate p110β as a possible PC-specific target therapy.
APA, Harvard, Vancouver, ISO, and other styles
7

Fedrigo, Carlos Alexandre. "Inibição da via PI3K-Akt em gliomas." Pontifícia Universidade Católica do Rio Grande do Sul, 2012. http://hdl.handle.net/10923/4518.

Full text
Abstract:
Made available in DSpace on 2013-08-07T19:05:17Z (GMT). No. of bitstreams: 1 000439149-Texto+Completo-0.pdf: 1490829 bytes, checksum: bd616615ee5265db0a960d6f77c8581d (MD5) Previous issue date: 2012
Glioblastoma multiforme (GMB) is the most malignant and common type of all astrocytic tumours. Current standard treatment for GBM patients involves maximum surgical resection of the tumour, followed by radiotherapy and chemotherapy, usually containing the alkylating agent Temozolomide (TMZ). Despite this aggressive combination therapy, the survival rate of GBM patients is still low. This work consisted in investigating the cytotoxic effects of Akt-inhibition by MK-2206 with irradiation (RT) and TMZ on in vitro human malignant glioma. Seven malignant glioma cell lines were cultured and tested for clonogenic survival, invasion inhibition, tumour spheroid growth and proliferation. The Akt-inhibitor MK-2206 and TMZ were added at different time treatments and in varying doses. Cultures were irradiated with single dose and with fractionated γ-irradiation. Cellular modulation of Akt and p-Akt were assessed by Western blot analysis. MK-2206 reduced the levels of phospho- Akt key protein in the PI3Kinase-Akt pathway, decreased cell survival, and inhibited invasion, proliferation and cell growth. The combination of MK-2206 and RT lead to enhanced inhibition of cell proliferation and invasion, which is not observed with RT alone. The radioenhancing effect of MK-2206 was most striking in inhibition of spheroid volume growth by fractionated RT; the radiosensitizing effect of MK-2206 was stronger than that of TMZ. MK-2206 enhanced the in vitro effects of RT and TMZ in terms of decreased cell survival, invasion, proliferation and growth in malignant glioma. Effects could be ascribed to inhibition of PI3K-Akt pathway.
O Glioblastoma multiforme (GBM) é o tipo mais maligno e mais comum de todos tumores astrocíticos. O tratamento atual para pacientes de GBM envolve máxima remoção cirúrgica, seguida de radio e quimioterapia, normalmente com o agente alquilante Temozolamida (TMZ). Apesar da agressividade da terapia combinada, o tempo de sobrevivência dos pacientes ainda é baixo. Este trabalho procurou investigar os efeitos citotóxicos do inibidor de Akt MK-2206 em combinação com irradiação (RT) e TMZ em um painel de células de gliomas humanos. Sete linhagens de glioma foram cultivadas e testadas em ensaio de sobrevivência clonogênica, inibição de invasão, e modelos de proliferação e crescimento de volume em esferóides. O inibidor MK-2206 e TMZ foram adicionados em diferentes tempos de tratamento e diferentes doses. As culturas foram irradiadas com doses únicas ou em terapias fracionadas com irradiação γ. A modulação celular de Akt e fosfo-Akt foi checada via Western Blot. O composto MK-2206 reduziu a fosforilação da proteína chave Akt na via PI3K, diminuindo a sobrevivência celular e inibindo invasão, proliferação e crescimento celular. A combinação de MK-2206 com RT levou a uma maior inibição de invasão e proliferação, o que não é observado somente com a RT. O efeito radiosensível de MK-2206 foi ainda maior na inibição do volume dos esferóides em terapia combinada com RT fracionada, sendo ainda maior do que o efeito combinado com TMZ. MK-2206 aumentou os efeitos in vitro de RT e TMZ em termos de redução de sobrevivência celular, invasão, proliferação e crescimento celular em gliomas malignos. Os efeitos podem ser atribuídos a inibição da via PI3KAkt.
APA, Harvard, Vancouver, ISO, and other styles
8

Ramos, Delgado Carmen Fernanda. "Exploring PI3K signalling dynamics in pancreatic cancer." Thesis, Toulouse 3, 2020. http://www.theses.fr/2020TOU30152.

Full text
Abstract:
Les PI3K sont des enzymes qui phosphorylent le groupe hydroxyl en position 3 des phosphatidylinositols comme le PIP2 ou le PI. Ces lipides sont impliqués dans de nombreux processus cellulaires tels que la croissance, la prolifération, la motilité, l'autophagie et le trafic cellulaire. Chez les mammifères, il y a 8 isoformes de PI3K et elles sont regroupées en trois classes (I, II et III) en fonction de leur structure et spécificité du substrat. Les PI3K de classe I sont les mieux caractérisées et impliquées dans le cancer. Les rôles oncogéniques des PI3K de classe II et III restent méconnus. La voie PI3K/Akt est fréquemment suractivée dans les cancers et est corrélée à un mauvais pronostic, particulièrement dans l'adénocarcinome canalaire pancréatique (PDAC). La mutation oncogénique de Kras est détectée dans plus de 90% des cas de PDAC et induit l'activation des voies effectrices, y compris de la voie PI3K. Le PDAC est l'un des cancers les plus mortels, caractérisé par un diagnostic tardif, une progression rapide et des options thérapeutiques limitées. Des études antérieures de l'équipe ont démontré que la PI3Kalpha, une PI3K de classe I, est cruciale dans les étapes précoces du PDAC. Néanmoins, son rôle dans la progression du PDAC reste inconnu. Ma thèse vise à élucider la dynamique de signalisation des PI3K dans le PDAC. J'ai commencé par caractériser le rôle de la PI3Kalpha dans la progression du PDAC et j'ai déterminé sa pertinence en tant que cible thérapeutique. Enfin, je montre des données préliminaires sur le rôle de Vps34, une PI3K de classe III, dans la physiologie des cellules acineuses et son rôle éventuel dans la cancérogenèse pancréatique. L'inactivation pharmacologique et génétique de PI3Kalpha in vitro démontre que cette PI3K contrôle les paramètres cellulaires qui régulent la progression des cellules tumorales pancréatiques, et ce quelles que soient leurs mutations génétiques. Ces résultats ont été validés in vivo dans le modèle murin appelé KPC. Ainsi, des souris KPC avec des taux élevés de cfDNA (cell free DNA, marqueur d'inflammation) et une tumeur détectée par échographie ont été traitées avec l'inhibiteur spécifique de PI3Kalpha, BYL-719. J'ai également comparé l'inhibition pharmacologique de PI3Kalpha avec l'inactivation génétique de PI3Kalpha dans l'épithélium pancréatique de souris KPC (réalisé avec des souris génétiquement modifiées). L'inhibition de la PI3Kalpha in vivo, diminue le volume tumoral, prolonge la survie et retarde la dissémination métastatique. L'effet anti-métastatique des inhibiteurs de PI3Kalpha a été validé par une injection de cellules cancéreuse pancréatiques dans la veine caudale avec ou sans traitement avec du BYL-719. L'inhibition de la PI3Kalpha a également diminué l'infiltration des macrophages protumoraux, suggérant un rôle dans la réponse immunitaire, facteur connu de progression du PDAC. [...]
PI3Ks are enzymes that catalyse the phosphorylation of inositol phospholipids in the 3-position of the inositol ring. These substrates and products are involved in multiple cellular processes such as cell growth, proliferation, cell motility and cellular trafficking. In mammals, there are 8 isoforms of PI3Ks and they are grouped into three classes (class I, II and III) depending on their structure and substrate specificity. Class I PI3Ks are the best characterised and the most commonly implicated in cancer. Current evidence on the oncogenic roles of class II and class III PI3Ks is limited. The PI3K/Akt signalling pathway is frequently hyperactivated in cancers and is usually correlated to a poor prognosis, particularly in pancreatic ductal adenocarcinoma (PDAC). More than 90% of PDAC cases are driven by activating mutations in Kras, which then activate downstream effector-signalling pathways, including the PI3K pathway. PDAC is one of the most lethal cancers, characterised by a late-stage diagnosis, a rapid progression and limited therapeutic options. There is a dire need to find new biomarkers and to design novel therapeutics for PDAC management. Previous studies from the team demonstrated that PI3Kalpha, a class I PI3K, is crucial in the initial stages of PDAC. Nonetheless, its role during PDAC progression remains unknown. My PhD aims to elucidate PI3K signalling dynamics in PDAC. I focused on characterising the role of PI3Kalpha in PDAC progression and on determining its suitability as a therapeutic target. Additionally, I show preliminary data on the role of Vps34, a class III PI3K, in acinar cell physiology and its possible role in pancreatic carcinogenesis. The pharmacological and genetic inactivation of PI3Kalpha in vitro demonstrate that this PI3K isoform regulates parameters that drive pancreatic tumour cell progression regardless of oncogenic mutations. These effects are organ-specific; depending on the organ context, another class I PI3K isoform could drive the cancer progression. These results were then validated in vivo in the KPC mouse model used for preclinical testing of PDAC. KPC mice with high levels of cfDNA and a detected tumour via ultrasound imaging were treated with the PI3Kalpha-specific inhibitor, BYL-719. Likewise, I compared the pharmacological inhibition of PI3Kalpha with the genetic inactivation of PI3Kalpha in the pancreatic epithelium of KPC mice. Targeting PI3Kalpha in vivo, pharmacologically and genetically, decreases tumour volume, increases life expectancy and delays metastatic dissemination. To further support the anti-metastatic effect of PI3Kalpha, a tail vein assay was performed and the mice were also given BYL-719. This last experiment reproduced the previous results obtained with the other mouse models, reinforcing the role of PI3Kalpha in decreasing metastatic dissemination. Besides delaying metastatic dissemination, PI3Kalpha also decreased the infiltration of protumoral macrophages, suggesting a role for this isoform in shaping the immune response. [...]
APA, Harvard, Vancouver, ISO, and other styles
9

Karnes, Jonathan Burgess. "PI3K Class IIalpha Is Required for Autophagy." Thesis, Van Andel Research Institute, 2017. http://pqdtopen.proquest.com/#viewpdf?dispub=10268645.

Full text
Abstract:

Autophagy is a cellular recycling process in which cytoplasmic proteins and organelles are sequestered in a double membrane vesicle, delivered to the lysosome, and degraded following fusion of the two vesicles. A key part of the initiation signaling for autophagy is the generation of phosphoinositol 3-phosphate (P13P) by class III phosphoinositol 3-kinase also knows as Vps 34. In humans there are eight P13K isoforms divided into three classes, four class I enzymes, three class II enzymes, and a single class III enzyme. Of these eight enzymes, only the class III isoform is thought to participate directly in autophagic signaling. A quantitative microscopy based, loss-of-function survey of all eight P13K isoforms was used to determine their relative contribution to autophagic signaling, as measured by LC3 positive autophagic vesicles. As predicted, knockdown of P13K-class III reduced the number of autophagic vesicles in cells. Interestingly, knockdown of the P13K-class IIα isoform had an even more potent effect on reducing the number of autophagic vesicles than knockdown of P13K-class III. In follow up studies, knockdown of P13K-class IIα reduced endogenous LC3 conversion, caused the accumulation of p62 and lipid droplets, and colocalized with endosomal markers. These results suggest P13K-class IIα may act to promote autophagy through the shuttling of endosomal vesicles into the autophagic pathway and approaches to test this hypothesis will be discussed. The requirement of P13K-class IIα for autophagy is an important finding as it indicates a role for class II P13Ks in autophagy.

APA, Harvard, Vancouver, ISO, and other styles
10

Zunder, Eli Richard. "A yeast screen for PI3K inhibitor resistance." Diss., Search in ProQuest Dissertations & Theses. UC Only, 2009. http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqdiss&rft_dat=xri:pqdiss:3339211.

Full text
APA, Harvard, Vancouver, ISO, and other styles
More sources

Books on the topic "PI3K"

1

Dominguez-Villar, Margarita, ed. PI3K and AKT Isoforms in Immunity. Cham: Springer International Publishing, 2022. http://dx.doi.org/10.1007/978-3-031-06566-8.

Full text
APA, Harvard, Vancouver, ISO, and other styles
2

Dey, Nandini, Pradip De, and Brian Leyland-Jones, eds. PI3K-mTOR in Cancer and Cancer Therapy. Cham: Springer International Publishing, 2016. http://dx.doi.org/10.1007/978-3-319-34211-5.

Full text
APA, Harvard, Vancouver, ISO, and other styles
3

Ding, Lili. The roles of ERK1/2 and PI3K in abnormal vascular functions in angiotensin II-infused hypertensive rats. St. Catharines, Ont: Brock University, Faculty of Applied Health Science, 2005.

Find full text
APA, Harvard, Vancouver, ISO, and other styles
4

Pink: Ridiculously random collection of thoughts spurred by the color pink. OKC, OK: Rory, 2005.

Find full text
APA, Harvard, Vancouver, ISO, and other styles
5

Pick for users. Oxford [Oxfordshire]: Blackwell Scientific Publications, 1985.

Find full text
APA, Harvard, Vancouver, ISO, and other styles
6

PICK for users. 2nd ed. Oxford: Blackwell Scientific Publications, 1990.

Find full text
APA, Harvard, Vancouver, ISO, and other styles
7

Cheng, Peter. Hydroacoustic estimation of Fraser River pink salmon abundance and distribution at Mission, B.C., in 1987. Vancouver, B.C: Pacific Salmon Commission, 1991.

Find full text
APA, Harvard, Vancouver, ISO, and other styles
8

Dallas, Karl. Bricks in the wall. New York: Shapolsky, 1988.

Find full text
APA, Harvard, Vancouver, ISO, and other styles
9

Bricks in the wall. New York: Shapolsky, 1987.

Find full text
APA, Harvard, Vancouver, ISO, and other styles
10

Pink Floyd. [Paris]: EJL, 2000.

Find full text
APA, Harvard, Vancouver, ISO, and other styles
More sources

Book chapters on the topic "PI3K"

1

Okkenhaug, Klaus. "PI3K." In Encyclopedia of Medical Immunology, 851–54. New York, NY: Springer New York, 2014. http://dx.doi.org/10.1007/978-0-387-84828-0_44.

Full text
APA, Harvard, Vancouver, ISO, and other styles
2

Donato, Dominique M., Steven K. Hanks, Kenneth A. Jacobson, M. P. Suresh Jayasekara, Zhan-Guo Gao, Francesca Deflorian, John Papaconstantinou, et al. "PI3K." In Encyclopedia of Signaling Molecules, 1419. New York, NY: Springer New York, 2012. http://dx.doi.org/10.1007/978-1-4419-0461-4_101039.

Full text
APA, Harvard, Vancouver, ISO, and other styles
3

Isabelle, Plo. "PI3K Signaling." In Encyclopedia of Cancer, 1–6. Berlin, Heidelberg: Springer Berlin Heidelberg, 2015. http://dx.doi.org/10.1007/978-3-642-27841-9_4569-2.

Full text
APA, Harvard, Vancouver, ISO, and other styles
4

Plo, Isabelle. "PI3K Signaling." In Encyclopedia of Cancer, 3576–81. Berlin, Heidelberg: Springer Berlin Heidelberg, 2017. http://dx.doi.org/10.1007/978-3-662-46875-3_4569.

Full text
APA, Harvard, Vancouver, ISO, and other styles
5

Plo, Isabelle. "PI3K Signaling." In Encyclopedia of Cancer, 2887–92. Berlin, Heidelberg: Springer Berlin Heidelberg, 2011. http://dx.doi.org/10.1007/978-3-642-16483-5_4569.

Full text
APA, Harvard, Vancouver, ISO, and other styles
6

Thomas, Hala Elnakat, Sónia R. Pereira da Veiga, George Thomas, and Sara C. Kozma. "The PI3K-mTOR Pathway." In mTOR Inhibition for Cancer Therapy: Past, Present and Future, 19–45. Paris: Springer Paris, 2016. http://dx.doi.org/10.1007/978-2-8178-0492-7_2.

Full text
APA, Harvard, Vancouver, ISO, and other styles
7

Hawkins, Phillip T., Len R. Stephens, Sabine Suire, and Michael Wilson. "PI3K Signaling in Neutrophils." In Current Topics in Microbiology and Immunology, 183–202. Berlin, Heidelberg: Springer Berlin Heidelberg, 2010. http://dx.doi.org/10.1007/82_2010_40.

Full text
APA, Harvard, Vancouver, ISO, and other styles
8

Platt, Craig. "Activated PI3K-Delta Syndrome." In Genetic Syndromes, 1–4. Cham: Springer International Publishing, 2022. http://dx.doi.org/10.1007/978-3-319-66816-1_2-1.

Full text
APA, Harvard, Vancouver, ISO, and other styles
9

Caux, Manuella, Gaetan Chicanne, and Sonia Severin. "Class III PI3K Biology." In Current Topics in Microbiology and Immunology, 69–93. Cham: Springer International Publishing, 2022. http://dx.doi.org/10.1007/978-3-031-06566-8_3.

Full text
APA, Harvard, Vancouver, ISO, and other styles
10

Aytenfisu, Tihitina Y., Hannah M. Campbell, Mayukh Chakrabarti, L. Mario Amzel, and Sandra B. Gabelli. "Class I PI3K Biology." In Current Topics in Microbiology and Immunology, 3–49. Cham: Springer International Publishing, 2022. http://dx.doi.org/10.1007/978-3-031-06566-8_1.

Full text
APA, Harvard, Vancouver, ISO, and other styles

Conference papers on the topic "PI3K"

1

COMA, SILVIA, David T. Weaver, and Jonathan A. Pachter. "Abstract 663: The dual PI3K-δ/PI3K-γ inhibitor duvelisib inhibits signaling and proliferation of solid tumor cells expressing PI3K-δ and/or PI3K-γ." In Proceedings: AACR Annual Meeting 2020; April 27-28, 2020 and June 22-24, 2020; Philadelphia, PA. American Association for Cancer Research, 2020. http://dx.doi.org/10.1158/1538-7445.am2020-663.

Full text
APA, Harvard, Vancouver, ISO, and other styles
2

Cantley, L., and C. Cantley Lewis. "Abstract MS1-1: Targeting PI3K." In Abstracts: Thirty-Fifth Annual CTRC‐AACR San Antonio Breast Cancer Symposium‐‐ Dec 4‐8, 2012; San Antonio, TX. American Association for Cancer Research, 2012. http://dx.doi.org/10.1158/0008-5472.sabcs12-ms1-1.

Full text
APA, Harvard, Vancouver, ISO, and other styles
3

Scott, William J., Ningshu Liu, Andreas Hägebarth, Manfred Möwes, Ursula Mönning, Ulf Bömer, Dominik Mumberg, Franz von Nussbaum, Michael Brands, and Julien Lafranc. "Abstract 4851: Second generation 2,3-dihydroimidazo[1,2-c]quinazoline PI3K inhibitors: development of BAY 1082439, a novel balanced PI3Ká / PI3Kâ inhibitor." In Proceedings: AACR 107th Annual Meeting 2016; April 16-20, 2016; New Orleans, LA. American Association for Cancer Research, 2016. http://dx.doi.org/10.1158/1538-7445.am2016-4851.

Full text
APA, Harvard, Vancouver, ISO, and other styles
4

Adams, Julian. "Abstract IA19: Targeting PI3K-δ and PI3K-γ in hematological malignancies with duvelisib (IPI-145)." In Abstracts: AACR Special Conference: Targeting the PI3K-mTOR Network in Cancer; September 14-17, 2014; Philadelphia, PA. American Association for Cancer Research, 2015. http://dx.doi.org/10.1158/1538-8514.pi3k14-ia19.

Full text
APA, Harvard, Vancouver, ISO, and other styles
5

Blanco Aparicio, Carmen, Oliver Renner, Elena Gomez-Casero, Antonio Cebriá, Nuria Ajenjo, Enara Aguirre, David Cebrián, et al. "Abstract A275: Co-targeting PIM and PI3K/mTOR pathways with a single molecule: Novel orally available combined PIM/PI3K and PIM/PI3K/mTOR kinase inhibitors." In Abstracts: AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics--Oct 19-23, 2013; Boston, MA. American Association for Cancer Research, 2013. http://dx.doi.org/10.1158/1535-7163.targ-13-a275.

Full text
APA, Harvard, Vancouver, ISO, and other styles
6

Cantley, Lewis C. "Abstract IA22: PI3K and cancer metabolism." In Abstracts: Third AACR International Conference on Frontiers in Basic Cancer Research - September 18-22, 2013; National Harbor, MD. American Association for Cancer Research, 2013. http://dx.doi.org/10.1158/1538-7445.fbcr13-ia22.

Full text
APA, Harvard, Vancouver, ISO, and other styles
7

Spoerke, Jill, Carol O'Brien, Jenny Wu, Rupal Desai, Rajesh Patel, Rajiv Raja, Hartmut Koeppen, et al. "Abstract 4821: Biomarker evaluation In phase I clinical trials of selective PI3K and PI3K/mTOR inhibitors." In Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL. American Association for Cancer Research, 2012. http://dx.doi.org/10.1158/1538-7445.am2012-4821.

Full text
APA, Harvard, Vancouver, ISO, and other styles
8

Spoerke, Jill, Rupal Desai, Rajesh Patel, Jill Fredrickson, Yulei Wang, Gallia Levy, Steve Gendreau, et al. "Abstract 4567: Biomarker evaluation in phase I clinical trials of selective PI3K and PI3K/mTOR inhibitors." In Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC. American Association for Cancer Research, 2013. http://dx.doi.org/10.1158/1538-7445.am2013-4567.

Full text
APA, Harvard, Vancouver, ISO, and other styles
9

Nakanishi, Yoshito, Jill M. Spoerke, Mika Derynck, Jennifer O. Lauchle, Hartmut Koeppen, Jill Fredrickson, Joseph Ware, Garret Hampton, Yibing Yan, and Mark R. Lackner. "Abstract B03: Pharmacodynamic biomarker evaluation in phase I clinical trials of selective PI3K and PI3K/mTOR inhibitors." In Abstracts: AACR Special Conference: Targeting the PI3K-mTOR Network in Cancer; September 14-17, 2014; Philadelphia, PA. American Association for Cancer Research, 2015. http://dx.doi.org/10.1158/1538-8514.pi3k14-b03.

Full text
APA, Harvard, Vancouver, ISO, and other styles
10

Sherris, David, Philip A. Dennis, Willie Wilson, Shigeru Kawabata, Chunrong Yu, Giovanni Luca Gravina, Andrea Mancini, and Claudio Festuccia. "Abstract A23: Differentiation of PI3K/Akt/mTOR inhibition in cancer models using dual dissociative TORC1/TORC2 (P529), single dissociative TORC1 (rapalogs) and catalytic inhibitors (PI3K/Akt, PI3K/mTOR)." In Abstracts: AACR Special Conference: Targeting the PI3K-mTOR Network in Cancer; September 14-17, 2014; Philadelphia, PA. American Association for Cancer Research, 2015. http://dx.doi.org/10.1158/1538-8514.pi3k14-a23.

Full text
APA, Harvard, Vancouver, ISO, and other styles

Reports on the topic "PI3K"

1

Ilic, Nina. Approaching Resistance to Targeted Inhibition of PI3K in Breast Cancer. Fort Belvoir, VA: Defense Technical Information Center, October 2011. http://dx.doi.org/10.21236/ada555900.

Full text
APA, Harvard, Vancouver, ISO, and other styles
2

Akasheh, Rand, Mahenge Cuthbert, Faiza Kalam, Anita Adib, Stephanie Schulte, and Ting-Yuan David Cheng. Body Size and Body Composition in Relation to the PI3K/AKT/MTOR Pathway Informing Cancer Risk and Outcomes: A Systematic Review. INPLASY - International Platform of Registered Systematic Review and Meta-analysis Protocols, May 2024. http://dx.doi.org/10.37766/inplasy2024.5.0036.

Full text
APA, Harvard, Vancouver, ISO, and other styles
3

Hang, Fei, Rishalaiti Tayier, Ang Li, Yanjie Yuan, and Shunhua Wu. PTEN regulates arsenic-inducedn autophagy in PI3K/AKT/mTOR signaling pathway; A systematic review and meta-analysis of in vivo and in vitro studies. INPLASY - International Platform of Registered Systematic Review and Meta-analysis Protocols, January 2021. http://dx.doi.org/10.37766/inplasy2021.1.0012.

Full text
APA, Harvard, Vancouver, ISO, and other styles
4

Poloboc, Alina. Fancy Pink Goat. Intellectual Archive, December 2023. http://dx.doi.org/10.32370/iaj.2998.

Full text
Abstract:
"Fancy Pink Goat" is a contemporary art piece from the Fancy Collection, created in Spain in 2022. It is a vividly colorful painting dominated by pink and blue, which are the signature colors of the artist`s style. The painting features a fancy goat walking through the jungle with its elegant collar and abstract, long legs. Surrounding the Fancy Pink Goat are a variety of other unusual creatures inhabiting the jungle and keeping the goat company. The artist`s signature red high-heeled shoes are also present, adding a touch of sophistication and style to the painting. This artwork is an impressive example of the artist`s unique style, which blends elements of surrealism and abstraction to create a sense of fantasy and wonder. The overall effect is an intriguing and vibrant work of art that captures the viewer`s imagination. With its expert technique and distinctive style, "Fancy Pink Goat" is truly a gem in the Fancy Collection.
APA, Harvard, Vancouver, ISO, and other styles
5

Chen, Xiaole, Peng Wang, Yunquan Luo, Yi-Yu Lu, Wenjun Zhou, Mengdie Yang, Jian Chen, Zhi-Qiang Meng, and Shi-Bing Su. Therapeutic Efficacy Evaluation and Underlying Mechanisms Prediction of Jianpi Liqi Decoction for Hepatocellular Carcinoma. Science Repository, September 2021. http://dx.doi.org/10.31487/j.jso.2021.02.04.sup.

Full text
Abstract:
Objective: The aim of this study was to assess the therapeutic effects of Jianpi Liqi decoction (JPLQD) in hepatocellular carcinoma (HCC) and explore its underlying mechanisms. Methods: The characteristics and outcomes of HCC patients with intermediate stage B who underwent sequential conventional transcatheter arterial chemoembolization (cTACE) and radiofrequency ablation (RFA) only or in conjunction with JPLQD were analysed retrospectively. The plasma proteins were screened using label-free quantitative proteomics analysis. The effective mechanisms of JPLQD were predicted through network pharmacology approach and partially verified by ELISA. Results: Clinical research demonstrated that the Karnofsky Performance Status (KPS), traditional Chinese medicine (TCM) syndrome scores, neutropenia and bilirubin, median progression-free survival (PFS), and median overall survival (OS) in HCC patients treated with JPLQD were superior to those in patients not treated with JPLQD (all P<0.05). The analysis of network pharmacology, combined with proteomics, suggested that 52 compounds targeted 80 potential targets, which were involved in the regulation of multiple signaling pathways, especially affecting the apoptosis-related pathways including TNF, p53, PI3K-AKT, and MAPK. Plasma IGFBP3 and CA2 were significantly up-regulated in HCC patients with sequential cTACE and RFA therapy treated with JPLQD than those in patients not treated with JPLQD (P<0.001). The AUC of the IGFBP3 and CA2 panel, estimated using ROC analysis for JPLQD efficacy evaluation, was 0.867. Conclusion: These data suggested that JPLQD improves the quality of life, prolongs the overall survival, protects liver function in HCC patients, and exhibits an anticancer activity against HCC. IGFBP3 and CA2 panels may be potential therapeutic targets and indicators in the efficacy evaluation for JPLQD treatment, and the effective mechanisms involved in the regulation of multiple signaling pathways, possibly affected the regulation of apoptosis.
APA, Harvard, Vancouver, ISO, and other styles
6

Zelenak, Andrew J. Covercoat Pick-and-Place Robot Design. Office of Scientific and Technical Information (OSTI), August 2013. http://dx.doi.org/10.2172/1089458.

Full text
APA, Harvard, Vancouver, ISO, and other styles
7

Higgins, E., and V. Stanziani. Boster pick up electrode signal processing. Office of Scientific and Technical Information (OSTI), March 1988. http://dx.doi.org/10.2172/1150492.

Full text
APA, Harvard, Vancouver, ISO, and other styles
8

Barash, Itamar, and Robert E. Rhoads. Translational Mechanisms that Govern Milk Protein Levels and Composition. United States Department of Agriculture, November 2004. http://dx.doi.org/10.32747/2004.7586474.bard.

Full text
Abstract:
Original objectives: The long term objective of the project is to achieve higher content of protein in the milk of ruminants by modulating the translational machinery in the mammary gland. The first specific aim of the BARD proposal was to characterize responsiveness of various experimental systems to combination of lactogenic hormones and amino acids with particular emphasis on discrimination between the control of total protein synthesis and milk protein synthesis. Based on the results, we planned to proceed by characterizing the stage of protein synthesis in which the stimulation by lactogenic hormones and amino acid occur and finally we proposed to identify which components of the translation machinery are modified. Background to the topic: Milk protein is the most valuable component in milk, both for direct human consumption and for manufacturing cheese and other protein-based products. Attempts to augment protein content by the traditional methods of genetic selection and improved nutritional regimes have failed. The proposal was based on recent results suggesting that the limiting factor for augmenting protein synthesis in the bovine mammary gland is the efficiency of converting amino acids to milk proteins. Major conclusions, solutions, achievements: Insulin and prolactin synergistically stimulate â-casein mRNA translation by cytoplasmatic polyadenylation. The interaction between insulin and prolactin was demonstrated two decades ago as crucial for milk-protein synthesis, but the molecular mechanisms involved were not elucidated. We found in differentiated CID 9 mouse mammary epithelial cells line that insulin and prolactin synergistically increases the rate of milk protein mRNA translation. We focused on â-casein, the major milk protein, and found that the increase in â-casein mRNA translation was reflected in a shift to larger polysomes, indicating an effect on translational initiation. Inhibitors of the PI3K, mTOR, and MAPK pathways blocked insulin-stimulated total protein and â-casein synthesis but not the synergistic stimulation. Conversely, cordycepin, a polyadenylation inhibitor, abolished synergistic stimulation of protein synthesis without affecting insulin-stimulated translation. The poly(A) tract of â-casein mRNA progressively increased over 30 min of treatment with insulin plus prolactin. The 3’-untranslated region of â-casein mRNA was found to contain a cytoplasmic polyadenylation element (CPE), and in reporter constructs, this was sufficient for the translational enhancement and mRNA-specific polyadenylation. Furthermore, insulin and prolactin stimulated phosphorylation of cytoplasmic polyadenylation element binding protein (CPEB) but did not increase cytoplasmic polyadenylation.
APA, Harvard, Vancouver, ISO, and other styles
9

Cook, Lisa, and Chaleampong Kongcharoen. The Idea Gap in Pink and Black. Cambridge, MA: National Bureau of Economic Research, September 2010. http://dx.doi.org/10.3386/w16331.

Full text
APA, Harvard, Vancouver, ISO, and other styles
10

Higgins, E. Some issues concerning beam sensing pick-ups. Office of Scientific and Technical Information (OSTI), July 1987. http://dx.doi.org/10.2172/1150463.

Full text
APA, Harvard, Vancouver, ISO, and other styles
You might also be interested in the extended bibliographies on the topic 'PI3K' for particular source types:
Journal articles Dissertations / Theses Books
We offer discounts on all premium plans for authors whose works are included in thematic literature selections. Contact us to get a unique promo code!

To the bibliography