Rb Inhibits E2F-1-induced Cell Death in a LXCXE-dependent Manner by Active Repression

Pennaneach, Vincent; Barbier, Valérie; Regazzoni, Karine; Fotedar, Rati; Fotedar, Arun

doi:10.1074/jbc.m309809200

Cited by 9 publications

(4 citation statements)

References 56 publications

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“…Importantly, pRb also functions as an active transcriptional repressor by recruiting various cofactors, many of which are involved in remodeling chromatin (45). E2F1-induced apoptosis has been shown to occur by both transcription-dependent and -independent mechanisms (1,15,36,43), and can be inhibited by the expression of pRb (15,35 (47). Furthermore, aberrant apoptosis caused by homozygous pRb deletion in mice was shown to depend on E2F1 (47).…”

Section: Discussionmentioning

confidence: 99%

Involvement of the CDK2-E2F1 pathway in cisplatin cytotoxicity in vitro and in vivo

Megyesi²,

Safirstein³

et al. 2007

American Journal of Physiology-Renal Physiology

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is a key regulator that links cell cycle progression and cell death. E2F1 activity is controlled by Cdk2-cyclin complexes via several mechanisms, such as phosphorylation of retinoblastoma protein (pRb) to release E2F1, direct phosphorylation, and stable physical interaction. We have demonstrated that cisplatin cytotoxicity depends on Cdk2 activity, and Cdk2 inhibition protects kidney cells from cisplatin-induced cell death in vitro and in vivo. Now we show that E2F1 is an important downstream effector of Cdk2 that accumulates in mouse kidneys and in cultured mouse proximal tubular cells (TKPTS) after cisplatin exposure by a Cdk2-dependent mechanism. Direct inhibition of E2F1 by transduction with adenoviruses expressing an E2F1-binding protein (TopBP1) protected TKPTS cells from cisplatin-induced apoptosis, whereas overexpression of E2F1 caused cell death. Moreover, E2F1 knockout mice were markedly protected against cisplatin nephrotoxicity by both functional and histological criteria. Collectively, cisplatin-induced cell death is dependent on Cdk2 activity, which is at least partly through the Cdk2-E2F1 pathway both in vitro and in vivo.acute kidney injury; cell cycle; cell death CISPLATIN IS WIDELY USED to treat several types of solid tumors in cancer patients (9). Its clinical utility is limited by its nephrotoxicity, to which renal proximal tubule epithelial cells are especially sensitive (37,42). Multiple mechanisms are implicated in cisplatin-induced nephrotoxicity, which results in tubular cell death by both apoptosis and necrosis (16,30,32,53) and in acute loss of kidney function.We and other groups showed in vivo that many normally quiescent kidney cells enter the cell cycle after cisplatin administration, as indicated by an increase in nuclear proliferating cell nuclear antigen (PCNA) levels, as well as [ 3 H]thymidine and bromodeoxyuridine (BrdU) incorporation into nuclear DNA (30,31). Coincident with increased cell cycle activity, cisplatin administration induces upregulation of p21, a cyclindependent kinase (Cdk) inhibitor (31). This protein is a positive effector on the fate of cisplatin-exposed renal tubule cells in vivo and in vitro (30, 38), and we reported that the mechanism of p21 protection is by direct inhibition of Cdk2 activity (51). Recently, we demonstrated that cisplatin cytotoxicity depends on Cdk2 activity, and Cdk2 inhibition protected kidney cells from cisplatin-induced cell death in vitro and in vivo (39). The mechanism of Cdk2 involvement in cell death is the subject of this report. Cdk2 is a kinase participating in cell cycle progression and is an upstream regulator of E2F1. E2F1 plays an important role in coordinating events connected with both cell cycle progression and cell death. This led us to hypothesize that E2F1 may participate in the Cdk2-dependent cell death pathway(s) induced by cisplatin.We show here that E2F1 accumulation correlated with cisplatin exposure and required Cdk2 activity both in cultured mouse proximal tubular cells (TKPTS) and in mouse kidneys. Direct inh...

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Section: Discussionmentioning

confidence: 99%

Involvement of the CDK2-E2F1 pathway in cisplatin cytotoxicity in vitro and in vivo

Megyesi²,

Safirstein³

et al. 2007

American Journal of Physiology-Renal Physiology

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“…It has been reported that RB1 interacts with E2F1 through its M domain by recognizing the “LXCXE” motif of E2F1. [ 31 ] We found that there was a conserved “LXCXE” motif in the N‐terminus of CBX3 (Figure 4H ). We constructed a mutant (Flag‐CBX3 delta LDCPE) of CBX3 that lacked the “LXCXE” motif (Figure 4H,I ).…”

Section: Resultsmentioning

confidence: 99%

Targeting CBX3 with a Dual BET/PLK1 Inhibitor Enhances the Antitumor Efficacy of CDK4/6 Inhibitors in Prostate Cancer

Liang,

Yang,

Zeng

et al. 2023

Advanced Science

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The development of castration‐resistant prostate cancer (CRPC) is a significant factor that reduces life expectancy among patients with prostate cancer. Previously, it is reported that CDK4/6 inhibitors can overcome the resistance of CRPC to BET inhibitors by destabilizing BRD4, suggesting that the combination of CDK4/6 inhibitors and BET inhibitors is a promising approach for treating CRPC. In this study, candidates that affect the combined antitumor effect of CDK4/6 inhibitors and BET inhibitors on CRPC is aimed to examine. The data demonstrates that CBX3 is abnormally upregulated in CDK4/6 inhibitors‐resistant cells. CBX3 is almost positively correlated with the cell cycle in multiple malignancies and is downregulated by BET inhibitors. Mechanistically, it is showed that CBX3 is transcriptionally upregulated by BRD4 in CRPC cells. Moreover, it is demonstrated that CBX3 modulated the sensitivity of CRPC to CDK4/6 inhibitors by binding with RB1 to release E2F1. Furthermore, it is revealed that PLK1 phosphorylated CBX3 to enhance the interaction between RB1 and CBX3, and desensitize CRPC cells to CDK4/6 inhibitors. Given that BRD4 regulates CBX3 expression and PLK1 affects the binding between RB1 and CBX3, it is proposed that a dual BRD4/PLK1 inhibitor can increase the sensitivity of CRPC cells to CDK4/6 inhibitors partially through CBX3.

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“…In another model suggested by Fotedar and collaborators [167], active repression of cell cycle promoting genes and apoptotic genes is mediated by different classes of Rb-LXCXE-associated proteins [167]. Whereas some genes, such as cyclin E and DHFR are generally repressed by recruitment of Rb-E2F1/HDAC complexes and deacetylation of histone termini [25], other genes, such as p73, which is required for p53-independent E2F-1-induced cell death, are repressed by Rb-E2F1 in association with RF-Cp145, the large subunit of the Replication Factor C. RF-Cp145 is an ATPase, and this enzymatic activity is required to elicit Rb-mediated active repression.…”

Section: Dual Role For Rbmentioning

confidence: 95%

“…Whereas some genes, such as cyclin E and DHFR are generally repressed by recruitment of Rb-E2F1/HDAC complexes and deacetylation of histone termini [25], other genes, such as p73, which is required for p53-independent E2F-1-induced cell death, are repressed by Rb-E2F1 in association with RF-Cp145, the large subunit of the Replication Factor C. RF-Cp145 is an ATPase, and this enzymatic activity is required to elicit Rb-mediated active repression. Therefore, it is envisioned that RF-Cp145 in complex with Rb/E2F induces a repressive chromatin configuration by an ATPdependent remodeling process shown for SWI-SNF ATPase complexes [167,168]. This model is supported by observations that implicate HDAC repression of E2F-regulated promoters in the G1 phase of the cell cycle and SWI/SNF in the absence of HDAC at the transition to the S-phase [reviewed in 18,25].…”

Section: Dual Role For Rbmentioning

confidence: 97%

Rb/E2F: A two-edged sword in the melanocytic system

Halaban

2005

Cancer Metastasis Rev

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Rb is a tumor suppressor that represses the expression of E2F regulated genes required for cell cycle progression. It is inactivated in melanomas and other cancer cells by phosphorylation catalyzed by persistent cyclin dependent kinase (CDK) activity. CDK activity is sustained in melanoma cells mostly by the elimination of the CDK inhibitor p16INK4A and by high levels of cyclins whose expression is maintained by stimuli emanating from activated cell surface receptors and/or mutated intracellular intermediates, such as N-Ras and B-Raf. However, Rb also suppresses the expression of apoptosis genes, and its presence protects normal melanocytes from cell death. Its high expression in human melanoma cells and tumors suggests a similar role in malignant cells as well. The differential release and suppression of E2F transcriptional activity is likely to depend on promoter-specific E2F/Rb interaction. Phosphorylated Rb is displaced from cell cycle genes but not from others. In addition, Rb gene repression is dependent on the nature of Rb-E2F interaction and the activity of the Rb-bound proteins recruited to the promoter. Deciphering the differences in Rb/E2F complex formation in normal and malignant melanocytes is likely to shed light on the mechanism by which Rb can exert tumor suppressing and promoting activities in this cellular system. The Rb/E2F pathway provides opportunities for efficient therapy at multiple levels. Novel drugs can reactivate Rb potential to suppress growth cycle promoting genes. In addition, the high E2F transcriptional activity in melanoma cells can be exploited to deliver cytotoxic molecules specifically to tumors, sparing the normal tissues.

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Rb Inhibits E2F-1-induced Cell Death in a LXCXE-dependent Manner by Active Repression

Cited by 9 publications

References 56 publications

Involvement of the CDK2-E2F1 pathway in cisplatin cytotoxicity in vitro and in vivo

Involvement of the CDK2-E2F1 pathway in cisplatin cytotoxicity in vitro and in vivo

Targeting CBX3 with a Dual BET/PLK1 Inhibitor Enhances the Antitumor Efficacy of CDK4/6 Inhibitors in Prostate Cancer

Rb/E2F: A two-edged sword in the melanocytic system

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