Regulation of PML-dependent transcriptional repression by pRB and low penetrance pRB mutants

Abstract

The retinoblastoma protein (pRB) is thought to suppress tumorigenesis, in part, through interactions with E2F transcription factors. However, certain low penetrance pRB mutants substantially reduce tumor incidence despite having a minimal ability to bind E2F. These low penetrance mutants retain the ability to induce a senescence-like state, suggesting that they may suppress tumorigenesis through a senescence-associated process. Here, we identify a novel pRB function that is associated with senescence and which is retained by non-E2F binding low penetrance pRB mutants. It was found that pRB and these mutants substantially increased the production of PML nuclear bodies (NBs). In keeping with the role of PML in transcriptional repression, pRB also promoted PML-dependent transcriptional repression by the c-Myc antagonist Mad1. In a series of pRB-p130 chimeric proteins, the ability to increase NB production correlated with the ability to induce a senescence-like phenotype. However, neither NB formation nor PML function were required for pRB to induce the senescencelike response. Together, these observations indicate that a pRB-induced increase in PML NB formation is coordinated with, but separable from, the pRB-induced senescence program. The data further suggest that PML may contribute to an E2F-independent tumor suppressor function of pRB.

Pocket proteins and cell cycle control

“…This notion has come from evidence that several 'low-penetrance' pRB mutants retain a partial ability to suppress retinoblastoma despite that they are defective in binding to E2F (Otterson et al, 1997;Harbour, 2001). Various low penetrance pRB mutants retain abilities to induce p27, to induce PML nuclear bodies, to augment differentiation-associated gene expression, to suppress Ras signaling, and to cooperate with hLin-9 in differentiation (Sellers et al, 1998;Lee et al, 1999;Fang et al, 2002;Ji et al, 2004;Gagrica et al, 2004), suggesting that one or more of these effects might contribute to retinoblastoma suppression.…”

“…For example, pRB can induce the formation of PML nuclear bodies (Fang et al, 2002), which have widespread effects on cell proliferation, differentiation, and survival (Salomoni and Pandolfi, 2002). pRB can also suppress Ras signaling (Lee et al, 1999) and augment expression of differentiation-associated genes (Sellers et al, 1998;Thomas et al, 2001).…”

RB and cell cycle progression

“…pRb can inhibit proliferation through an E2F-independent mechanism. For example, pRb can induce the formation of promyelocytic leukemia (PML) nuclear bodies (Fang et al, 2002), increase p27 expression (see above), suppress Ras signaling (Lee et al, 2002) and cooperate with hLin-9, a protein that is involved, similar to pRb, in suppressing transformation but in an E2F-independent manner (Gagrica et al, 2004).…”

Human Cytomegalovirus UL97 Kinase Activity Is Required for the Hyperphosphorylation of Retinoblastoma Protein and Inhibits the Formation of Nuclear Aggresomes

“…In addition, IE1 directs the dispersion of PML bodies through the SUMOylation of PML (42) and the deletion of IE1 leads to a broad defect in virus delayed-early gene expression (20). The role of PML as a tumor suppressor was recently shown to involve both the p53 and retinoblastoma protein (RB) pathways and has previously been reviewed (22,61).Ofinterest,RBformsstablecomplexeswiththeunphosphorylated form of PML (3) and results in increased numbers of PML bodies (15). This interaction appears to be functional, since PML increases the transcriptional repression mediated by RB (36) and the two function together to promote hematopoiesis (40).…”