RB1 in cancer: Different mechanisms of RB1 inactivation and alterations of pRb pathway in tumorigenesis

Abstract

Loss of RB1 gene is considered either a causal or an accelerating event in retinoblastoma. A variety of mechanisms inactivates RB1 gene, including intragenic mutations, loss of expression by methylation and chromosomal deletions, with effects which are species-and cell typespecific. RB1 deletion can even lead to aneuploidy thus greatly increasing cancer risk. The RB1gene is part of a larger gene family that includes RBL1 and RBL2, each of the three encoding structurally related proteins indicated as pRb, p107, and p130, respectively. The great interest in these genes and proteins springs from their ability to slow down neoplastic growth. pRb can associate with various proteins by which it can regulate a great number of cellular activities. In particular, its association with the E2F transcription factor family allows the control of the main pRb functions, while the loss of these interactions greatly enhances cancer development. As RB1 gene, also pRb can be functionally inactivated through disparate mechanisms which are often tissue specific and dependent on the scenario of the involved tumor suppressors and oncogenes. The critical role of the context is complicated by the different functions played by the RB proteins and the E2F family members. In this review, we want to emphasize the importance of the mechanisms of RB1/pRb inactivation in inducing cancer cell development. The review is divided in three chapters describing in succession the mechanisms of RB1 inactivation in cancer cells, the alterations of pRb pathway in tumorigenesis and the RB protein and E2F family in cancer.

The Drosophila retinoblastoma protein, Rbf1, induces a debcl and drp1-dependent mitochondrial apoptosis.

“…The retinoblastoma susceptibility gene (Rb) is a tumor suppressor gene mutated in a large variety of cancer (Di Fiore et al, 2013). Its tumor suppressive activity is at least partially dependent on its ability to induce cell cycle arrest.…”

MDM2/MDMX: Master negative regulators for p53 and RB

“…The growth suppressive function of the retinoblastoma protein (RB) is inhibited by direct inactivating mutations, or more commonly by changes in expression of its upstream regulators, including overexpression of cyclin D1, activating mutations in cyclin-dependent protein kinase 4 (CDK4), and inactivating mutations in p16 INK4A (inhibitor of cyclin-dependent kinase type 4, also called INK4A). 1 In addition, RB is inactivated by the viral oncoprotein E7, which promotes RB instability, and by E1A or SV40T, which disrupt the interaction between RB and the E2F family of DNA binding transcription factors (E2F). 1 We have shown that mouse double minute 2 homolog (MDM2) directly binds to the C-pocket of RB, leading to disruption of RB-E2F interaction and accelerated RB degradation.…”

“…1 In addition, RB is inactivated by the viral oncoprotein E7, which promotes RB instability, and by E1A or SV40T, which disrupt the interaction between RB and the E2F family of DNA binding transcription factors (E2F). 1 We have shown that mouse double minute 2 homolog (MDM2) directly binds to the C-pocket of RB, leading to disruption of RB-E2F interaction and accelerated RB degradation. 2,3 In our recent study, we demonstrated that double minute X human homolog, (MDMX, also known as MDM4) can also bind to and promote RB degradation in an MDM2-dependent manner, thereby promoting tumor growth.…”

Regulation of E2F1-induced apoptosis by poly(ADP-ribosyl)ation

“…Because the loss of RB1 causes subsequent hyperactivation (or deregulation) of E2F1, which should theoretically activate both cell-cycle progression and apoptosis, 19 we hypothesized that cancer cells constitutively expressing deregulated E2F1 must have an RB1-independent mechanism that does not allow E2F1 to induce apoptosis during serum starvation, but that instead leaves E2F1-induced cell-cycle progression intact.…”