The role of PI 3‐kinase p110β in AKT signally, cell survival, and proliferation in human prostate cancer cells

Hill, Karen M.; Kalifa, Sara; Das, Jharna R.; Bhatti, Tahira; Williams, Danielle; Taliferro-Smith, La Tonia; Marzo, Angelo M. De

doi:10.1002/pros.21108

Cited by 38 publications

(28 citation statements)

References 42 publications

(50 reference statements)

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“…Yap cKO mice were reported to have more cardiomyocyte apoptosis 3 , and their cardiomyocyte regenerative capacity was impaired 5 . Because the PI3K-AKT pathway promotes both cell proliferation and survival 22 , we hypothesized that Pik3cb overexpression ameliorates the Yap cKO phenotype by increasing cardiomyocyte proliferation, decreasing apoptosis, or both.…”

Section: Resultsmentioning

confidence: 99%

Pi3kcb Links Hippo-YAP and PI3K-AKT Signaling Pathways to Promote Cardiomyocyte Proliferation and Survival

Lin

Zhou

Gise

et al. 2015

Circulation Research

246

237

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Rationale YAP, the nuclear effector of Hippo signaling, regulates cellular growth and survival in multiple organs, including the heart, by interacting with TEAD sequence specific DNA-binding proteins. Recent studies showed that YAP stimulates cardiomyocyte proliferation and survival. However, the direct transcriptional targets through which YAP exerts its effects are poorly defined. Objective To identify direct YAP targets that mediate its’ mitogenic and anti-apoptotic effects in the heart. Methods and Results We identified direct YAP targets by combining differential gene expression analysis in YAP gain- and loss-of-function with genome-wide identification of YAP bound loci using chromatin immunoprecipitation and high throughput sequencing. This screen identified Pik3cb, encoding p110β, a catalytic subunit of phosphoinositol-3-kinase (PI3K), as a candidate YAP effector that promotes cardiomyocyte proliferation and survival. YAP and TEAD occupied a conserved enhancer within the first intron of Pik3cb, and this enhancer drove YAP-dependent reporter gene expression. Yap gain- and loss-of-function studies indicated that YAP is necessary and sufficient to activate the PI3K-Akt pathway. Like Yap, Pik3cb gain-of-function stimulated cardiomyocyte proliferation, and Pik3cb knockdown dampened YAP mitogenic activity. Reciprocally, impaired heart function in Yap loss-of-function was significantly rescued by AAV-mediated Pik3cb expression. Conclusion : Pik3cb is a crucial direct target of YAP, through which the YAP activates PI3K-AKTpathway and regulates cardiomyocyte proliferation and survival.

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Section: Resultsmentioning

confidence: 99%

Pi3kcb Links Hippo-YAP and PI3K-AKT Signaling Pathways to Promote Cardiomyocyte Proliferation and Survival

Lin

Zhou

Gise

et al. 2015

Circulation Research

246

237

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“…Previous studies have identified p110β as a key player in tumor formation, particularly in PTEN-null models and cell lines (22)(23)(24)(25). It also has been shown that p110β, as well as p110δ and p110γ, are transforming in their wild-type state (15); the authors noted the alignment of K342 in p110β with N345 in p110α and hypothesized that p110β might be similar to the p110α-N345K mutant.…”

Section: Discussionmentioning

confidence: 99%

A biochemical mechanism for the oncogenic potential of the p110β catalytic subunit of phosphoinositide 3-kinase

Dbouk¹,

Pang²,

Fiser

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Class I PI3-kinases signal downstream of receptor tyrosine kinases and G protein-coupled receptors and have been implicated in tumorigenesis. Although the oncogenic potential of the PI3-kinase subunit p110α requires its mutational activation, other p110 isoforms can induce transformation when overexpressed in the wildtype state. In wild-type p110α, N345 in the C2 domain forms hydrogen bonds with D560 and N564 in the inter-SH2 (iSH2) domain of p85, and mutations of p110α or p85 that disrupt this interface lead to increased basal activity and transformation. Sequence analysis reveals that N345 in p110α aligns with K342 in p110β. This difference makes wild-type p110β analogous to a previously described oncogenic mutant, p110α-N345K. We now show that p110β is inhibited by p85 to a lesser extent than p110α and is not differentially inhibited by wild-type p85 versus p85 mutants that disrupt the C2-iSH2 domain interface. Similar results were seen in soft agar and focus-formation assays, where p110β was similar to p110α-N345K in transforming potential. Inhibition of p110β by p85 was enhanced by a K342N mutation in p110β, which led to decreased activity in vitro, decreased basal Akt and ribosomal protein S6 kinase (S6K1) activation, and decreased transformation in NIH 3T3 cells. Moreover, unlike wild-type p110β, p110β-K342N was differentially regulated by wild-type and mutant p85, suggesting that the inhibitory C2-iSH2 interface is functional in this mutant. This study shows that the enhanced transforming potential of p110β is the result of its decreased inhibition by p85, due to the disruption of an inhibitory C2-iSH2 domain interface. oncogenic mutation | oncogenic transformation | lipid kinase P I3-kinases are important regulators of cell growth and survival, and they mediate responses to extracellular stimuli through receptor tyrosine kinases (RTKs) and G protein-coupled receptors (GPCRs) (1). Disruption of normal PI3-kinase signaling is observed in cancer and many other diseases (1, 2). Class IA PI3-kinases are obligate heterodimeric proteins composed of a catalytic subunit (p110α, -β, -δ) and a regulatory subunit (p85α, p85β, p55α, p50α, and p55γ) (3). It had been suggested previously that class IA PI3-kinases function primarily downstream of RTKs, with the Src homology 2 (SH2) domains of p85 targeting the p85/p110 dimers to phosphorylated tyrosine residues in activated receptors or their adaptor molecules (1). However, recent data suggest that p110β is activated downstream of GPCRs, although it still is unclear whether p110β is activated only by GPCRs or by RTKs as well (4, 5).p85 and p110 are multidomain proteins that interact with each other and with multiple upstream regulators and downstream effectors (6). p85 consists of an N-terminal Src homology 3 (SH3) domain, two proline-rich regions surrounding a breakpoint cluster region (BCR) homology region that can bind to small GTPases, and two SH2 domains flanking the inter-SH2 (iSH2) antiparallel coiled coil. Class IA p110 subunits are composed of an adaptorbindin...

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“…Up-regulation of this pathway in prostate cancer can also take place through activating mutations of Akt1 (Boormans et al 2008), or through activation of the p110b isoform of PI3K (Hill et al 2010;Lee et al 2010). The functional consequences of Akt/mTOR pathway activation are particularly relevant for castration-resistant prostate cancer, as has been shown in genetically engineered mouse models, in gain-of-function studies with orthotopic grafting or tissue recombination models, as well as in human cell lines (Majumder et al 2003;Uzgare and Isaacs 2004;Gao et al 2006a;Xin et al 2006).…”

Section: Signaling Pathways-akt/mtor and Mapk Signalingmentioning

confidence: 99%

Molecular genetics of prostate cancer: new prospects for old challenges

Shen¹,

2010

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Despite much recent progress, prostate cancer continues to represent a major cause of cancer-related mortality and morbidity in men. Since early studies on the role of the androgen receptor that led to the advent of androgen deprivation therapy in the 1940s, there has long been intensive interest in the basic mechanisms underlying prostate cancer initiation and progression, as well as the potential to target these processes for therapeutic intervention. Here, we present an overview of major themes in prostate cancer research, focusing on current knowledge of principal events in cancer initiation and progression. We discuss recent advances, including new insights into the mechanisms of castration resistance, identification of stem cells and tumor-initiating cells, and development of mouse models for preclinical evaluation of novel therapuetics. Overall, we highlight the tremendous research progress made in recent years, and underscore the challenges that lie ahead.

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The role of PI 3‐kinase p110β in AKT signally, cell survival, and proliferation in human prostate cancer cells

Abstract: Our results support the concept that p110beta appears to be the predominant functional class I PI 3-kinase isoform in prostate cancer cells.

Cited by 38 publications

References 42 publications

Pi3kcb Links Hippo-YAP and PI3K-AKT Signaling Pathways to Promote Cardiomyocyte Proliferation and Survival

Pi3kcb Links Hippo-YAP and PI3K-AKT Signaling Pathways to Promote Cardiomyocyte Proliferation and Survival

A biochemical mechanism for the oncogenic potential of the p110β catalytic subunit of phosphoinositide 3-kinase

Molecular genetics of prostate cancer: new prospects for old challenges

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