PTEN regulates the ubiquitin-dependent degradation of the CDK inhibitor p27KIP1 through the ubiquitin E3 ligase SCFSKP2

Mamillapalli, Ramanaiah; Gavrilova, Nadia J.; Mihaylova, Valia T.; Tsvetkov, Lyuben; Wu, Hong; Zhang, Hui; Sun, Hong

doi:10.1016/s0960-9822(01)00065-3

Cited by 211 publications

(179 citation statements)

References 11 publications

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“…The balance between PI3K and PTEN has also been shown to regulate the expression level of SKP2, a ubiquitin E3 ligase that acts as a component of the SCF ligase. The expression levels of PTEN and SKP2 are inversely related (Mamillapalli et al, 2001). However, SKP2 appears to be highly selective and only targets a handful of proteins involved in cell cycle regulation, such as p27 Kip1 and p21 CIP1 (Reed, 2003), and so is unlikely to play a significant role in regulating the expression levels of our target proteins.…”

Section: Discussionmentioning

confidence: 99%

Modulation of specific protein expression levels by PTEN: identification of AKAP121, DHFR, G3BP, Rap1 and RCC1 as potential targets of PTEN

et al. 2005

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The tumor suppressor PTEN is mutated in a high percentage of human cancers, and is implicated in pathways regulating cell growth, proliferation, survival, and migration. Despite significant advances, our understanding of its mechanisms of action remains incomplete. We have used a high-throughput proteomic immunoblotting approach to identify proteins whose expression levels are modulated by PTEN. Out of over 800 proteins screened, 22 proteins showed significant changes in expression. Five proteins that exhibited two-fold or greater changes in expression level were further characterized. AKAP121 and G3BP expression was reduced, while dihydrofolate reductase (DHFR), Rap1 and RCC1 expression was elevated in response to PTEN expression in a PTEN-null T-cell leukemia line. The phosphatase activity of PTEN was required for these effects. However, direct inhibition of PI-3 Kinase could mimic PTEN in modulating expression of DHFR, G3BP, Rap1 and RCC1, but not AKAP121. Real-time PCR showed that the effects of PTEN were primarily post-transcriptional, and would not have been revealed by mRNA-based screens. We conclude from these data that PTEN can modulate the expression level of a number of different proteins. The identified proteins have the potential to serve as previously unrecognized effectors of PTEN, and suggest the existence of additional complexity in the modes by which PTEN can regulate cellular biology.

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Section: Discussionmentioning

confidence: 99%

Modulation of specific protein expression levels by PTEN: identification of AKAP121, DHFR, G3BP, Rap1 and RCC1 as potential targets of PTEN

et al. 2005

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“…Akt enhances the degradation of p27 by the proteasome-dependent pathway by upregulating SKP2 mRNA levels. SKP2 is a key component of the SCF/SKP2 ubiquitin ligase that mediates p27 degradation in a cyclin E/CDK2 dependent phosphorylation (Hara et al, 2001;Mamillapalli et al, 2001;Pagano et al, 1995). Previously it was shown that Akt-mediated phosphorylation of p27 at thr-157 also causes the relocation of p27 to the cytoplasm, thus relieving the nuclear substrates from p27 inhibition and enhancing the cell cycle progression (Shin et al, 2002).…”

Section: Pi3-k/akt Pathway and Cell Cycle Progressionmentioning

confidence: 99%

Cell survival, cell death and cell cycle pathways are interconnected: Implications for cancer therapy

Maddika¹,

Ande²,

Panigrahi³

et al. 2007

Drug Resistance Updates

408

302

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The partial cross-utilization of molecules and pathways involved in opposing processes like cell survival, proliferation and cell death, assures that mutations within one signaling cascade will also affect the other opposite process at least to some extent, thus contributing to homeostatic regulatory circuits. This review highlights some of the connections between opposite-acting pathways. Thus, we discuss the role of cyclins in the apoptotic process, and in the regulation of cell proliferation. CDKs and their inhibitors like the INK4-family (p16 Ink4a , p15 Ink4b , p18 Ink4c , p19 Ink4d ), and the Cip1/Waf1/Kip1-2-family (p21 Cip1/Waf1 , p27 Kip1 , p57 Kip2 ) are shown both in the context of proliferation regulators and as contributors to the apoptotic machinery. Bcl2-family members (i.e. Bcl2, Bcl-X L Mcl-1 L ; Bax, Bok/Mtd, Bak, and Bcl-X S ; Bad, Bid, Bim EL , Bmf, Mcl-1 S ) are highlighted both for their apoptosis-regulating capacity and also for their effect on the cell cycle progression. The PI3-K/Akt cell survival pathway is shown as regulator of cell metabolism and cell survival, but examples are also provided where aberrant activity of the pathway may contribute to the induction of apoptosis. Myc/Mad/Max proteins are shown both as a powerful S-phase driving complex and as apoptosis-sensitizers. We also discuss multifunctional proteins like p53 and Rb (RBL1/p107, RBL2/p130) both in the context of G 1 -S transition and as apoptotic triggers. Finally, we reflect on novel therapeutic approaches that would involve redirecting over-active survival and proliferation pathways towards induction of apoptosis in cancer cells.

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“…It has been shown that PTEN induces accumulation of the p27 protein at a post-transcriptional level (Mamillapalli et al, 2001). In contrast, PTEN-induced downregulation of vascular endothelial growth factor (VEGF) results from decreased activity of the VEGF promoter (Koul et al, 2002;Gomez-Manzano et al, 2003).…”

Section: Pten Inhibits Igf-ir Precursor Translation In Prostate Cancementioning

confidence: 99%

PTEN inhibits cell proliferation and induces apoptosis by downregulating cell surface IGF-IR expression in prostate cancer cells

et al. 2004

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PTEN is a tumor suppressor gene that is frequently mutated in human tumors. It functions primarily as a lipid phosphatase and plays a key role in the regulation of phosphatidylinositol-3 0 -kinase. PTEN appears to play a crucial role in modulating apoptosis by reducing the levels of PtdIns(3,4,5)P3, a phospholipid that activates AKT, a central regulator of apoptosis. To understand the role of PTEN in regulating cell proliferation and apoptosis, we stably overexpressed PTEN in PC3 cells, which are prostate cancer cells that lack PTEN. Overexpression of PTEN in two different clones inhibited cell proliferation and increased serum starvation-induced apoptosis, as compared to control cells. Interestingly, PTEN overexpression resulted in a 44-60% reduction in total insulinlike growth factor-I receptor (IGF-IR) protein levels and a 49-64% reduction in cell surface IGF-IR expression.[ 35 S]methionine pulse experiments in PC3 cells overexpressing PTEN demonstrated that these cells synthesize significantly lower levels of the IGF-IR precursor, whereas PTEN overexpression had no effect on IGF-IR degradation. Taken together, our results show that PTEN can regulate cell proliferation and apoptosis through inhibition of IGF-IR synthesis. These results have important implications for understanding the roles of PTEN and the IGF-IR in prostate cancer cell tumorigenesis.

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PTEN regulates the ubiquitin-dependent degradation of the CDK inhibitor p27KIP1 through the ubiquitin E3 ligase SCFSKP2

Cited by 211 publications

References 11 publications

Modulation of specific protein expression levels by PTEN: identification of AKAP121, DHFR, G3BP, Rap1 and RCC1 as potential targets of PTEN

Modulation of specific protein expression levels by PTEN: identification of AKAP121, DHFR, G3BP, Rap1 and RCC1 as potential targets of PTEN

Cell survival, cell death and cell cycle pathways are interconnected: Implications for cancer therapy

PTEN inhibits cell proliferation and induces apoptosis by downregulating cell surface IGF-IR expression in prostate cancer cells

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