pRB and p107/p130 are required for the regulated expression of different sets of E2F responsive genes
ABSTRACT The activity of the E2F transcription factor is controlled by physical association with the retinoblastoma protein (pRB) and two related proteins, p107 and p130. The pRB family members are thought to control different aspects of E2F activity, but it has been unclear what the respective functions of these proteins might be. To dissect the specific functions of pRB, p107, and p130 we have investigated how the expression of E2F-regulated genes is changed in cultures of primary cells lacking each of these family members. Whereas no changes were found in the expression of E2F-target genes in cells lacking either p107 or p130, deregulated expression of E2F targets was seen in cells lacking pRB and in cells lacking both p107 and p130. Surprisingly, the genes that were disregulated in these two settings were completely different. These findings show that pRB and p107/p130 indeed provide different functions in E2F regulation and identify target genes that are dependent on pRB family proteins for their normal expression.
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- "Remarkably, deletion of any one member of the family results in up-regulation of the others. In particular, loss of p130 leads to increased expression of p107 in quiescence, even though its expression is normally quite low at this stage of the cell cycle (Hurford et al. 1997). For these reasons , it has been challenging to delineate boundaries between the respective roles for pRB, p107, and p130 in cell cycle control. "
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ABSTRACT: The Hippo pathway coordinates organ size and cell proliferation. The retinoblastoma family of proteins regulates progression through the G0/G1 phase of the cell cycle. Disruption of either pathway contributes to cancer formation. Three recent studies in Genes & Development reveal how cellular proliferation is coordinated between these pathways. Here we discuss the implications of these studies and the new questions that they raise.Genes & development 05/2011; 25(9):889-94. DOI:10.1101/gad.2050411 · 12.64 Impact Factor
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- "Thus our results not only reveal the unique specificity of RB for E2F replication targets but a strict concordance between the nature of genes regulated by RB and the specific phenotype associated with RB loss – i.e. unscheduled DNA replication during senescence but not quiescence. Although previous studies hinted that RB family proteins can regulate different E2F targets (Hurford et al., 1997) and that loss of RB can ultimately lead to increased loading of replications complexes on chromatin (Srinivasan et al., 2007), the selectivity of RB towards repressing replication genes was not appreciated. "
ABSTRACT: The RB protein family (RB, p107, and p130) has overlapping and compensatory functions in cell-cycle control. However, cancer-associated mutations are almost exclusively found in RB, implying that RB has a nonredundant role in tumor suppression. We demonstrate that RB preferentially associates with E2F target genes involved in DNA replication and is uniquely required to repress these genes during senescence but not other growth states. Consequently, RB loss leads to inappropriate DNA synthesis following a senescence trigger and, together with disruption of a p21-mediated cell-cycle checkpoint, enables extensive proliferation and rampant genomic instability. Our results identify a nonredundant RB effector function that may contribute to tumor suppression and reveal how loss of RB and p53 cooperate to bypass senescence.Cancer cell 04/2010; 17(4):376-87. DOI:10.1016/j.ccr.2010.01.023 · 23.89 Impact Factor
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- "The intricacy of the system is further complicated by the existence of several E2Fs and pocket protein family members, with the ability to form repressive or activating complexes with chromatin modifiers. Additional complexity arises from the fact that each member of the E2F or pocket protein family is characterized by a specific cellular and temporal pattern of gene expression, and some E2Fs have the ability to modulate the levels of other members as well as p107, p21, and Cdk1 (Furukawa et al., 1999; Hurford et al., 1997; Iavarone and Massague, 1999; Johnson et al., 1993; Neuman et al., 1994 ; Smith et al., 1998; Takahashi et al., 2000; Tommasi and Pfeifer, 1995; Wu et al., 2001; Zhu et al., 1995b). In this review, we shall first introduce the cell-specific temporal pattern of expression and then analyze the phenotype in the CNS of knockout animals lacking single or multiple E2F (Table 1) and Rb family members to better understand their individual role in proliferation, survival, and differentiation in the nervous system. "
ABSTRACT: Development of the central nervous system (CNS) requires the generation of neuronal and glial cell subtypes in appropriate numbers, and this demands the careful coordination of cell-cycle exit, survival, and differentiation. The E2F/Rb pathway is critical for cell-cycle regulation and also modulates survival and differentiation of distinct cell types in the developing and adult CNS. In this review, we first present the specific temporal patterns of expression of the E2F and Rb family members during CNS development and then discuss the genetic ablation of single or multiple members of these two families. Overall, the available data suggest a time-dependent and cell-context specific role of E2F and Rb family members in the developing and adult CNS.Glia 11/2009; 58(4):377-90. DOI:10.1002/glia.20933 · 6.03 Impact Factor