Stabilization of E2F1 protein by MDM2 through the E2F1 ubiquitination pathway

Zhang, Zhuo; Wang, Hui; Li, Mao; Rayburn, Elizabeth R.; Agrawal, Sudhir; Zhang, Ruiwen

doi:10.1038/sj.onc.1208814

Cited by 118 publications

(119 citation statements)

References 53 publications

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“…In a previous study (19), the loss of E2F-1 following Nutlin treatment seemed to be mediated by its increased ubiquitination and subsequent proteosomal degradation. MDM2 increases the E2F-1 protein half-life by inhibiting the ubiquitination of E2F-1 by displacing the E3 ubiquitin ligase SCF Skp2 from E2F-1 (15). We can venture the hypothesis that phosphorylation of MDM2 by CK1␣ should allow its binding with E2F-1, which is thus protected against degradation.…”

Section: Discussionmentioning

confidence: 99%

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CK1α Plays a Central Role in Mediating MDM2 Control of p53 and E2F-1 Protein Stability

Huart

MacLaine

Meek

et al. 2009

Journal of Biological Chemistry

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The ubiquitin ligase murine double minute clone 2 (MDM2) mediates ubiquitination and degradation of the tumor suppressor p53. The activation and stabilization of p53 by contrast is maintained by enzymes catalyzing p53 phosphorylation and acetylation. Casein kinase 1 (CK1) is one such enzyme; it stimulates p53 after transforming growth factor-␤ treatment, irradiation, or DNA virus infection. We analyzed whether CK1 regulates p53 protein stability in unstressed conditions. Depletion of CK1 using small interfering RNA or inhibition of CK1 using the kinase inhibitor (D4476) activated p53 and destabilized E2F-1, indicating that steady-state levels of these proteins are controlled by CK1. Co-immunoprecipitation of endogenous CK1 with MDM2 occurred in undamaged cells, indicating the existence of a stable multiprotein complex, and as such, we evaluated whether the MDM2 Nutlin had similar pharmacological properties to the CK1 inhibitor D4476. Indeed, D4476 or Nutlin treatments resulted in the same p53 and E2F-1 steady-state protein level changes, indicating that the MDM2⅐CK1 complex is both a negative regulator of p53 and a positive regulator of E2F-1 in undamaged cells. Although the treatment of cells with D4476 resulted in a partial p53-dependent growth arrest, the induction of p53-independent apoptosis by D4476 suggested a critical role for the MDM2⅐CK1 complex in maintaining E2F-1 anti-apoptotic signaling. These data highlighting a pharmacological similarity between MDM2 and CK1 small molecule inhibitors and the fact that CK1 and MDM2 form a stable complex suggest that the MDM2⅐CK1 complex is a component of a genetic pathway that co-regulates the stability of the p53 and E2F-1 transcription factors.

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Section: Discussionmentioning

confidence: 99%

“…Furthermore, CK1␣ depletion after siRNA treatment led to a significant decrease of E2F-1 ( Fig. 1), which might be explained by disruption of the stabilizing binding between E2F-1 and MDM2, which has been shown to displace other ubiquitin ligases from E2F-1 (15).…”

Section: Ck1␣ Depletionmentioning

confidence: 99%

CK1α Plays a Central Role in Mediating MDM2 Control of p53 and E2F-1 Protein Stability

Huart

MacLaine

Meek

et al. 2009

Journal of Biological Chemistry

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“…Other mechanisms are also involved in E2F1 stability, such as degradation by SCF SKP2 E3 ligase, which is antagonized by MDM2 (Zhang et al, 2005). Further studies are needed to elucidate the role that p53/MDM2 plays in the regulation of E2F1.…”

Section: Nutlin-3a Enhances E2f1-induced Apoptosismentioning

confidence: 99%

Mouse double minute antagonist Nutlin-3a enhances chemotherapy-induced apoptosis in cancer cells with mutant p53 by activating E2F1

et al. 2006

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MDM2 is a critical negative regulator of the p53 tumor suppressor protein. Recently, small-molecule antagonists of MDM2, the Nutlins, have been developed to inhibit the p53-MDM2 interaction and activate p53 signaling. However, half of human cancers have mutated p53 and they are resistant to Nutlin treatment. Here, we report that treatment of the p53-mutant malignant peripheral nerve sheath (MPNST) and p53-null HCT116 cells with cisplatin (Cis) and Nutlin-3a induced a degree of apoptosis that was significantly greater than either drug alone. Nutlin-3a also increased the cytotoxicity of both carboplatin and doxorubicin in a series of p53-mutant human tumor cell lines. In the human dedifferentiated liposarcoma cell line (LS141) and the p53 wild-type HCT116 cells, Nutlin-3a induced downregulation of E2F1 and this effect appeared to be proteasome dependent. In contrast, in MPNST and HCTp53À/À cells, Nutlin-3a inhibited the binding of E2F1 to MDM2 and induced transcriptional activation of free E2F1 in the presence of Cis-induced DNA damage. Downregulation of E2F1 by small interfering RNA significantly decreased the level of apoptosis induced by Cis and Nutlin-3a treatment. Moreover, expression of a dominant-negative form of E2F1 rescued cells from apoptosis, whereas cells overexpressing wildtype E2F1 showed an increase in cell death. This correlated with the induction of the proapoptotic proteins p73a and Noxa, which are both regulated by E2F1. These results indicate that antagonism of MDM2 by Nutlin-3a in cells with mutant p53 enhances chemosensitivity in an E2F1-dependent manner. Nutlin-3a therefore may provide a therapeutic benefit in tumors with mutant p53 provided it is combined with chemotherapy.

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“…Effects of MAGE-A11 on HDM2 Stabilization and E2F1 Transcriptional Activity-A well known function of ARF that contributes to cell cycle arrest is the inhibition of HDM2 E3 ubiquitin ligase activity, which results in up-regulation of p53 to promote cell cycle arrest or apoptosis (23-27, 52) and downregulation of E2F1 activation of genes involved in cell cycle progression (53)(54)(55). This suggests that one mechanism by which cancer cells interfere with the tumor suppressor activity of ARF is through the stabilization of HDM2.…”

Section: Mage-a11 Versus ␤-Actin Band Intensity Is Shown In the Rightmentioning

confidence: 99%

Post-translational Down-regulation of Melanoma Antigen-A11 (MAGE-A11) by Human p14-ARF Tumor Suppressor

Minges

Grossman

Zhang

et al. 2015

Journal of Biological Chemistry

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Background: Melanoma antigen-A11 (MAGE-A11) is a primate-specific steroid receptor coregulator and proto-oncogene expressed at increased levels in castration-resistant prostate cancer. Results: Human p14-ARF tumor suppressor promotes the proteasomal degradation of MAGE-A11 independent of ubiquitination. Conclusion: MAGE-A11 is post-translationally down-regulated by the p14-ARF tumor suppressor. Significance: Increased levels of MAGE-A11 associated with low p14-ARF promote the development of castration-resistant prostate cancer.

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Stabilization of E2F1 protein by MDM2 through the E2F1 ubiquitination pathway

Cited by 118 publications

References 53 publications

CK1α Plays a Central Role in Mediating MDM2 Control of p53 and E2F-1 Protein Stability

CK1α Plays a Central Role in Mediating MDM2 Control of p53 and E2F-1 Protein Stability

Mouse double minute antagonist Nutlin-3a enhances chemotherapy-induced apoptosis in cancer cells with mutant p53 by activating E2F1

Post-translational Down-regulation of Melanoma Antigen-A11 (MAGE-A11) by Human p14-ARF Tumor Suppressor

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