The atypical E2F family member E2F7 couples the p53 and RB pathways during cellular senescence

ArticleinGenes & development 26(14):1546-57 · July 2012with37 Reads
Impact Factor: 10.80 · DOI: 10.1101/gad.196238.112 · Source: PubMed

Oncogene-induced senescence is an anti-proliferative stress response program that acts as a fail-safe mechanism to limit oncogenic transformation and is regulated by the retinoblastoma protein (RB) and p53 tumor suppressor pathways. We identify the atypical E2F family member E2F7 as the only E2F transcription factor potently up-regulated during oncogene-induced senescence, a setting where it acts in response to p53 as a direct transcriptional target. Once induced, E2F7 binds and represses a series of E2F target genes and cooperates with RB to efficiently promote cell cycle arrest and limit oncogenic transformation. Disruption of RB triggers a further increase in E2F7, which induces a second cell cycle checkpoint that prevents unconstrained cell division despite aberrant DNA replication. Mechanistically, E2F7 compensates for the loss of RB in repressing mitotic E2F target genes. Together, our results identify a causal role for E2F7 in cellular senescence and uncover a novel link between the RB and p53 pathways.


Available from: Xiaowo Wang, Aug 26, 2015
    • "Cellular senescence is a distinct cell state involving permanent cell-cycle arrest of cells that remain viable and metabolically active , which is characterized by a discrete transcriptional profile (Shay and Roninson 2004). The TP53 protein controls cellular senescence by activating a number of transcriptional targets that include Cdkn1a, Pml, Pai1, and E2f7 (Pearson et al. 2000; Kortlever et al. 2006; Aksoy et al. 2012 ), some of which (e.g., Cdkn1a) are notable for additional function in cell-cycle regulation . Senescence is often associated with, and is thought to suppress, premalignant lesions preventing their progression to overt malignancy (Collado et al. 2005; Mooi and Peeper 2006). "
    [Show abstract] [Hide abstract] ABSTRACT: The fundamental biological importance of the Tp53 gene family is highlighted by its evolutionary conservation for more than one billion years dating back to the earliest multicellular organisms. The TP53 protein provides essential functions in the cellular response to diverse stresses and safeguards maintenance of genomic integrity, and this is manifest in its critical role in tumor suppression. The importance of Tp53 in tumor prevention is exemplified in human cancer where it is the most frequently detected genetic alteration. This is confirmed in animal models, in which a defective Tp53 gene leads inexorably to cancer development, whereas reinstatement of TP53 function results in regression of established tumors that had been initiated by loss of TP53. Remarkably, despite extensive investigation, the specific mechanisms by which TP53 acts as a tumor suppressor are yet to be fully defined. We review the history and current standing of efforts to understand these mechanisms and how they complement each other in tumor suppression.
    Preview · Article · May 2016 · Cold Spring Harbor Perspectives in Medicine
    • "This regulatory mechanism is most likely important during late S, G2, and M phases to coordinate the downregulation of E2F target genes. In addition, it might be also relevant during DNA damage, because previous studies have shown that E2F7/8 expression increases during DNA damage434445 and APC/C Cdh1 activity becomes reactivated in G2 cells with DNA damage [46,47]. Further support for an APC/C Cdh1 -E2F feedback loop is provided by the fact that the Emi1-encoding gene FBXO5 and the CDK2-activating genes CCNA2 and CCNE1/2 are known target genes of the activator E2F1–3 [33,48,49]. "
    [Show abstract] [Hide abstract] ABSTRACT: E2F transcription factors control the oscillating expression pattern of multiple target genes during the cell cycle. Activator E2Fs, E2F1–3, induce an upswing of E2F targets, which is essential for the G1-to-S phase transition, whereas atypical E2Fs, E2F7 and E2F8, mediate a downswing of the same targets during late S, G2, and M phases. Expression of atypical E2Fs is induced by E2F1–3, but it is unknown how atypical E2Fs are inactivated in a timely manner. Here, we demonstrate that E2F7 and E2F8 are substrates of the anaphase-promoting complex/cyclosome (APC/C). Removal of CDH1, or mutating the CDH1-interacting KEN boxes, stabilized E2F7/8 from anaphase onwards and during G1. Expressing KEN mutant E2F7 during G1 impairs S phase entry and eventually results in cell death. Furthermore, we show that E2F8, but not E2F7, interacts also with APC/CCdc20. Importantly, atypical E2Fs can activate APC/CCdh1 by repressing its inhibitors cyclin A, cyclin E, and Emi1. In conclusion, we discovered a feedback loop between atypical E2Fs and APC/CCdh1 , which ensures balanced expression of cell cycle genes and normal cell cycle progression. Keywords anaphase-promoting complex; CDH1; cell cycle
    Full-text · Article · Feb 2016 · EMBO Reports
    • "Why some WD/DDLS cells undergo senescence and others do not following CDK4 inhibition was not clear. We were unable to link this to the activity of SCF skp2 , the accumulation of p21 or E2F7, the expression of p300 or twist, or the accumulation of DNA damage, telomere attrition, or production of ROS, all well established inducers of senescence whether p53 dependent or independent171819 50]. Because senescence is a preferred outcome of cell cycle exit induced by chemotherapy, and CDK4 inhibitors have achieved Breakthrough Therapy Designation from the FDA and have had some success in treating patients with WD/DDLS, it seemed important to understand this. "
    [Show abstract] [Hide abstract] ABSTRACT: CDK4 inhibitors (CDK4i) earned Breakthrough Therapy Designation from the FDA last year and are entering phase III clinical trials in several cancers. However, not all tumors respond favorably to these drugs. CDK4 activity is critical for progression through G1 phase and into the mitotic cell cycle. Inhibiting this kinase induces Rb-positive cells to exit the cell cycle into either a quiescent or senescent state. In this report, using well-differentiated and dedifferentiated liposarcoma (WD/DDLS) cell lines, we show that the proteolytic turnover of MDM2 is required for CDK4i-induced senescence. Failure to reduce MDM2 does not prevent CDK4i-induced withdrawal from the cell cycle but the cells remain in a reversible quiescent state. Reducing MDM2 in these cells drives them into the more stable senescent state. CDK4i-induced senescence associated with loss of MDM2 is also observed in some breast cancer, lung cancer and glioma cell lines indicating that this is not limited to WD/DDLS cells in which MDM2 is overexpressed or in cells that contain wild type p53. MDM2 turnover depends on its E3 ligase activity and expression of ATRX. Interestingly, in seven patients the changes in MDM2 expression were correlated with outcome. These insights identify MDM2 and ATRX as new regulators controlling geroconversion, the process by which quiescent cells become senescent, and this insight may be exploited to improve the activity of CDK4i in cancer therapy.
    Full-text · Article · Jan 2015 · Oncotarget
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