Negative cell cycle regulator 14-3-3σ stabilizes p27 Kip1 by inhibiting the activity of PKB/Akt

Yang, Heng; Zhang, Y.; Zhao, Ruihua; Wen, Yong; Fournier, Keith F.; Wu, Hongyun; Diaz, José I.; Laronga, Christine; Lee, Mong Hong

doi:10.1038/sj.onc.1209481

Cited by 49 publications

(36 citation statements)

References 42 publications

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“…Because 14-3-3 j blocks Cdc2 activity by sequestering Cdc2 from the nucleus, 14-3-3 j may regulate Akt kinase activity through controlling subcellular localization. However, we found that 14-3-3 j did not dramatically affect the distribution of Akt (43). The detailed mechanism behind CTMP-mediated Akt inhibition has not been determined yet (42).…”

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confidence: 66%

DNA Damage–Induced Protein 14-3-3 σ Inhibits Protein Kinase B/Akt Activation and Suppresses Akt-Activated Cancer

et al. 2006

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confidence: 66%

DNA Damage–Induced Protein 14-3-3 σ Inhibits Protein Kinase B/Akt Activation and Suppresses Akt-Activated Cancer

et al. 2006

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“…Moreover, AKT can phosphorylate p27 on Thr157, thus delaying its nuclear import (Liang et al, 2002) and facilitating its cytoplasmic sequestration into complexes with cyclin D-CDKs (Chu et al, 2008), whereas AKT inhibition leads to p27 accumulation and nuclear localization (Motti et al, 2005;Yang et al, 2006). This mechanism seems to function also in MM cell lines in which phospho-AKT inhibition mediated by the PI3 kinase inhibitor LY294002 induces an increase in p27 levels Mikami et al, 2010) and in its nuclear/cytoplasmic ratio (Supplementary Figure S2).…”

Section: Src Inhibition Increases P27 Nuclear Localizationmentioning

confidence: 96%

New pyrazolo[3,4-d]pyrimidine SRC inhibitors induce apoptosis in mesothelioma cell lines through p27 nuclear stabilization

et al. 2011

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Malignant mesothelioma (MM) is a highly aggressive tumor of the serous membranes for which there is currently no effective curative modality. Recent data suggest that hyperactivation of the tyrosine kinase SRC has a key role in MM development and therefore this kinase represents an important molecular target for MM therapy. We tested new pyrazolo [3,4-d]pyrimidine SRC inhibitors on a panel of MM cell lines expressing the active form of SRC. These SRC inhibitors exerted a significant proapoptotic effect on MM cells without affecting the normal mesothelial cell line MET-5A, supporting a possible use of these SRC inhibitors for a safe treatment of MM. We also showed that SRC inhibitor-induced apoptosis occurred concomitantly with an increase in the nuclear stability of the cyclindependent kinase inhibitor p27. This finding is remarkable considering that loss of nuclear p27 expression is a wellestablished adverse prognostic factor in MM, and p27 nuclear localization is crucial for its tumor-suppressive function. Consistently, SRC inhibition seems to promote the increase in p27 nuclear level also by inactivating the AKT kinase and downregulating cyclin D1, which would otherwise delay p27 nuclear import and provoke its cytoplasmic accumulation. To determine whether p27 stabilization has a direct role in apoptosis induced by SRC inhibition, we stably silenced the CDKN1B gene, encoding p27, in MSTO-211H and REN mesothelioma cells by transduction with lentiviral vectors expressing short hairpin RNAs against the CDKN1B transcript. Strikingly, p27 silencing was able to suppress the apoptosis induced by these SRC inhibitors in both MM cell lines, suggesting that p27 has a crucial proapoptotic role in MM cells treated with SRC inhibitors. Our findings reveal a new mechanism, dependent on p27 nuclear stabilization, by which SRC inhibition can induce apoptosis in MM cells and provide a new rationale for the use of SRC inhibitors in MM therapy.

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“…16 Akt downregulation leads to p27 accumulation. 23,24 Akt phosphorylates p27 to create a site for 14-3-3 binding, which, in turn, leads to nuclear export. 25,26 p27 is then decreased in p57-induced mice (-dox) compared with control mice (+dox) (Fig.…”

Section: Discussionmentioning

confidence: 99%

CDK inhibitor p57^Kip2 is downregulated by Akt during HER2-mediated tumorigenicity

et al. 2013

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Kip1 (p27), a cyclin-dependent kinase (CDK) inhibitor, and in causing p27 cytoplasmic localization.6 HER2 can also activate Akt to phosphorylate p21 at threonine 145, resulting in the cytoplasmic location of p21, another CDK inhibitor, which prevents p21's growth inhibitory activity.7 Although Akt is known to phosphorylate and regulate several important substrates, many of its substrates remain to be characterized.HER2/neu oncogene is frequently deregulated in cancers, and the (pI3K)-Akt signaling is one of the major pathways in mediating HeR2/neu oncogenic signal. p57Kip2 , an inhibitor of cyclin-depependent kinases, is pivotal in regulating cell cycle progression, but its upstream regulators remain unclear. Here we show that the HeR2-Akt axis is linked to p57 Kip2 regulation, and that Akt is a negative regulator of p57Kip2 . ectopic expression of Akt can decrease the expression of p57 Kip2 , while Akt inhibition leads to p57Kip2 stabilization. Mechanistic studies show that Akt interacts with p57 Kip2 and causes cytoplasmic localization of p57 Kip2 . Akt phosphorylates p57 on Ser 282 or thr310. Akt activity results in destabilization of p57 by accelerating turnover rate of p57 and enhancing p57 ubiquitination. Importantly, the negative impact of HeR2/Akt on p57 stability contributes to HeR2-mediated cell proliferation, transformational activity and tumorigenicity. p57 restoration can attenuate these defects caused by HeR2. Significantly, Kaplan-Meier analysis of tumor samples demonstrate that in tumors where HeR2 expression was observed, high expression levels of p57Kip2 were associated with better overall survival. these data suggest that HeR2/Akt is an important negative regulator of p57 Kip2 , and that p57 restoration in HeR2-overexpressing cells can reduce breast tumor growth. our findings indicate the applicability of employing p57 regulation as a therapeutic intervention in HeR2-overexpressing cancers.

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Negative cell cycle regulator 14-3-3σ stabilizes p27 Kip1 by inhibiting the activity of PKB/Akt

Cited by 49 publications

References 42 publications

DNA Damage–Induced Protein 14-3-3 σ Inhibits Protein Kinase B/Akt Activation and Suppresses Akt-Activated Cancer

DNA Damage–Induced Protein 14-3-3 σ Inhibits Protein Kinase B/Akt Activation and Suppresses Akt-Activated Cancer

New pyrazolo[3,4-d]pyrimidine SRC inhibitors induce apoptosis in mesothelioma cell lines through p27 nuclear stabilization

CDK inhibitor p57^Kip2 is downregulated by Akt during HER2-mediated tumorigenicity

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Negative cell cycle regulator 14-3-3σ stabilizes p27 Kip1 by inhibiting the activity of PKB/Akt

Cited by 49 publications

References 42 publications

DNA Damage–Induced Protein 14-3-3 σ Inhibits Protein Kinase B/Akt Activation and Suppresses Akt-Activated Cancer

DNA Damage–Induced Protein 14-3-3 σ Inhibits Protein Kinase B/Akt Activation and Suppresses Akt-Activated Cancer

New pyrazolo[3,4-d]pyrimidine SRC inhibitors induce apoptosis in mesothelioma cell lines through p27 nuclear stabilization

CDK inhibitor p57Kip2 is downregulated by Akt during HER2-mediated tumorigenicity

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CDK inhibitor p57^Kip2 is downregulated by Akt during HER2-mediated tumorigenicity