Cell cycle control and beyond: emerging roles for the retinoblastoma gene family

Abstract

Rb family proteins (pRb/p105, Rb2/p130 and p107) play a key role in cell cycle control and are worthily involved in transcription repression and tumor suppression. The mechanisms of transcriptional activation and repression by the Rb gene family has been extensively investigated: pRb, pRb2/p130 and p107 interact with different E2F family factors and can inhibit E2F responsive promoters, interfering with progression of cell cycle, gene transcription, initiation of apoptotic process and cell differentiation. Recent studies have indicated that Rb and Rb2/p130 may be involved in cellular response to DNA damage events, by influencing the transcription of factors involved in DNA repair pathways. In particular, evidences suggest that Rb loss and target gene deregulation impacts on the repair of UV-induced pyrimidine pyrimidone photoproducts (6-4 PP) by regulating the expression of several DNA damage factors involved in UV DNA damage repair processes, including proliferating cell nuclear antigen. Ongoing studies are focused on the mechanisms by which Rb family genes drive cell cycle exit following DNA damage induction, and how Rb gene family's interaction with chromatin remodeling factors can influence DNA repair dynamics.

Members of a family of JmjC domain-containing oncoproteins immortalize embryonic fibroblasts via a JmjC domain-dependent process

“…In dividing cells, the DNA damage response is activated by telomere shortening, oxidative stress, the aberrant firing of replication origins, or by activated oncogenes (28). Signaling pathways activated by DNA damage target the Rb and p53 pathways and induce reversible or irreversible cell cycle arrest or apoptosis (25)(26)(27). To determine the mechanism by which Ndy1 prevents senescence, we examined the effects of its overexpression on the Rb and p53 pathways.…”

“…Ndy2, a homolog of Ndy1, also promotes immortalization of MEFs. Immortalization was linked to the selective phosphorylation of Rb (25) and the selective abrogation of the prosenescence activity of p21 CIP1 (26,29).…”

“…The activation of the Ink4a/ARF locus and the response to DNA damage, which are the main factors promoting senescence, target both the p53 and Rb pathways (25)(26)(27). To determine which pathway may be targeted by Ndy1, we examined the phosphorylation of Rb at Ser-807/811 and Ser-780 and the expression of p53 and its target p21 CIP1 in early-and late-passage MEFs infected with MigR1 and MigR1-based constructs of Ndy1 and ⌬JmjC-Ndy1.…”

A small molecule based on the pRb2/p130 spacer domain leads to inhibition of cdk2 activity, cell cycle arrest and tumor growth reduction in vivo

“…This family includes the product of the Rb susceptibility gene, the pRb/p105 protein and the related p107 and pRb2/130 proteins (Mayol et al, 1993;Du and Pogoriler, 2006;Merola et al, 2006). They share the ability to recruit chromatin-remodeling enzymes and their best characterized targets are the members of the E2F/DP family of transcription factors, generally referred to as E2F (Cinti et al, 2005;Tosi et al, 2005;Genovese et al, 2006;Macaluso et al, 2006;Purev et al, 2006). Both pRb2/p130 and p107 are able to bind cdk2/ cyclins A and E (Claudio et al, 1996).…”

Molecular targets of selenium in prostate cancer prevention (Review)

“…However, phosphorylation of Rb by Cdks (Cdk 4/6-cyclin d or Cdk 2-cyclin E) inactivates Rb, thereby releasing E2Fs. Free E2Fs then heterodimerize with their dNA-binding partners leading to transcriptional activation of growth-promoting genes (88)(89)(90)(91).…”