Regulation of the retinoblastoma–E2F pathway by the ubiquitin–proteasome system

Sengupta, Satyaki; Henry, R. William

doi:10.1016/j.bbagrm.2015.08.008

Cited by 37 publications

(27 citation statements)

References 127 publications

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“…In addition, post-translational modifications on E2F1 that subsequently alter its ubiquitylation patterns regulate both its cell cycle phase-specific degradation and its stabilization during DNA damage [1, 30]. E2F1 degradation at the onset of S/G2 is achieved through the action of several E3 ubiquitin ligases.…”

Section: Discussionmentioning

confidence: 99%

CDH1 regulates E2F1 degradation in response to differentiation signals in keratinocytes

Singh

Dagnino

2016

Oncotarget

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The E2F1 transcription factor plays key roles in skin homeostasis. In the epidermis, E2F1 expression is essential for normal proliferation of undifferentiated keratinocytes, regeneration after injury and DNA repair following UV radiation-induced photodamage. Abnormal E2F1 expression promotes nonmelanoma skin carcinoma. In addition, E2F1 must be downregulated for proper keratinocyte differentiation, but the relevant mechanisms involved remain poorly understood. We show that differentiation signals induce a series of post-translational modifications in E2F1 that are jointly required for its downregulation. Analysis of the structural determinants that govern these processes revealed a central role for S403 and T433. In particular, substitution of these two amino acid residues with non-phosphorylatable alanine (E2F1 ST/A) interferes with E2F1 nuclear export, K11- and K48-linked polyubiquitylation and degradation in differentiated keratinocytes. In contrast, replacement of S403 and T433 with phosphomimetic aspartic acid to generate a pseudophosphorylated E2F1 mutant protein (E2F1 ST/D) generates a protein that is regulated in a manner indistinguishable from that of wild type E2F1. Cdh1 is an activating cofactor that interacts with the anaphase-promoting complex/cyclosome (APC/C) ubiquitin E3 ligase, promoting proteasomal degradation of various substrates. We found that Cdh1 associates with E2F1 in keratinocytes. Inhibition or RNAi-mediated silencing of Cdh1 prevents E2F1 degradation in response to differentiation signals. Our results reveal novel regulatory mechanisms that jointly modulate post-translational modifications and downregulation of E2F1, which are necessary for proper epidermal keratinocyte differentiation.

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Section: Discussionmentioning

confidence: 99%

CDH1 regulates E2F1 degradation in response to differentiation signals in keratinocytes

Singh

Dagnino

2016

Oncotarget

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“…Phosphorylation is the most well-characterized post-translational modification of RB, particularly phosphorylation of Cdk/cyclin complexes, which plays a role in RB inhibition during cell cycle control [18]. However, only a few E3 ubiquitin ligase proteins have been reported as regulators of RB: during virus infection, cullin 2 is able to target RB for degradation via the human papillomavirus protein E7; SCF SKP2 is also able to target RB via the Epstein-Barr EBNA3C protein; and under non-viral infection conditions, RB is ubiquitinated by NRBE3 and MDM2 [19–23]. The regulatory activity of MDM2 and MDMX proteins on the tumor suppressor RB is becoming the subject of focus.…”

Section: Introductionmentioning

confidence: 99%

Dual function of MDM2 and MDMX toward the tumor suppressors p53 and RB

et al. 2016

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The orchestrated crosstalk between the retinoblastoma (RB) and p53 pathways contributes to preserving proper homeostasis within the cell. The deregulation of one or both pathways is a common factor in the development of most types of human cancer. The proto-oncoproteins MDMX and MDM2 are the main regulators of the well- known tumor suppressor p53 protein. Under normal conditions, MDM2 and MDMX inhibit p53, either via repression of its transcriptional activity by protein-protein interaction, or via polyubiquitination as a result of MDM2-E3 ubiquitin ligase activity, for which MDM2 needs to dimerize with MDMX. Under genotoxic stress conditions, both become positive regulators of p53. The ATM-dependent phosphorylation of MDM2 and MDMX allow them to bind p53 mRNA, these interactions promote p53 translation. MDM2 and MDMX are also being revealed as effective regulators of the RB protein. MDM2 is able to degrade RB by two different mechanisms, that is, by ubiquitin dependent and independent pathways. MDMX enhances the ability of MDM2 to bind and degrade RB protein. However, MDMX also seems to stabilize RB through interaction and competition with MDM2. Here, we will contextualize the findings that suggest that the MDM2 and MDMX proteins have a dual function on both p53 and RB.

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“…For example, this circuitry elevates levels of the MDM2 oncogene to minimize p53-mediated apoptosis [16, 18]. Likewise, the S-phase associated kinase 2 (SKP2) regulate cell cycle entry and is required for cone precursor and retinoblastoma cell proliferation [16, 28, 29]. Both MDM2 and SKP2 are themselves targets of AKT phosphorylation mediated activation, suggesting that activated AKT may also be part of this circuitry [30–33].…”

Section: Discussionmentioning

confidence: 99%

Retinoblastoma cells activate the AKT pathway and are vulnerable to the PI3K/mTOR inhibitor NVP-BEZ235

et al. 2017

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Retinoblastoma is a pediatric cancer of the retina most often caused by inactivation of the retinoblastoma (RB1) tumor suppressor gene. We previously showed that Rb1 loss cooperates with either co-activating the phosphatidylinositol 3-kinase (PI3K)/AKT pathway, or co-deleting Pten, to initiate retinoblastoma tumors in mice. The objectives of this study were to determine if the AKT pathway is activated in human retinoblastomas and the extent that anti-PI3K therapy induces apoptosis in retinoblastoma cells, alone or in combination with the DNA damaging drugs carboplatin and topotecan. Serial sections from human retinoblastoma tissue microarrays containing 27 tumors were stained with antibodies specific to p-AKT, Ki-67, forkhead box O1 (p-FOXO1), and ribosomal protein S6 (p-S6) using immunohistochemistry and each tumor sample scored for intensity. Human retinoblastoma tumors displayed significant correlation between p-AKT intensity with highly proliferative tumors (p = 0.008) that were also highly positive for p-FOXO1 (p = 0.002). Treatment with BEZ235, a dual PI3K/mTOR inhibitor, reduced phosphorylation levels of the AKT targets p-FOXO and p-S6 and effectively induced apoptosis the Y79 and Weri-1 human retinoblastoma cell lines and in vivo in our retinoblastoma mouse model. Long-term treatment with BEZ235 in vivo using our retinoblastoma-bearing mice induced apoptosis but did not significantly extend the lifespan of the mice. We then co-administered BEZ235 with topotecan and carboplatin chemotherapeutics in vivo, which more effectively induced apoptosis of retinoblastoma, but not normal retinal cells than either treatment alone. Our study has increased the variety of potentially effective targeted treatments that can be considered for human retinoblastoma.

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Regulation of the retinoblastoma–E2F pathway by the ubiquitin–proteasome system

Cited by 37 publications

References 127 publications

CDH1 regulates E2F1 degradation in response to differentiation signals in keratinocytes

CDH1 regulates E2F1 degradation in response to differentiation signals in keratinocytes

Dual function of MDM2 and MDMX toward the tumor suppressors p53 and RB

Retinoblastoma cells activate the AKT pathway and are vulnerable to the PI3K/mTOR inhibitor NVP-BEZ235

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