Rb/E2F: A two-edged sword in the melanocytic system

Abstract

Rb is a tumor suppressor that represses the expression of E2F regulated genes required for cell cycle progression. It is inactivated in melanomas and other cancer cells by phosphorylation catalyzed by persistent cyclin dependent kinase (CDK) activity. CDK activity is sustained in melanoma cells mostly by the elimination of the CDK inhibitor p16INK4A and by high levels of cyclins whose expression is maintained by stimuli emanating from activated cell surface receptors and/or mutated intracellular intermediates, such as N-Ras and B-Raf. However, Rb also suppresses the expression of apoptosis genes, and its presence protects normal melanocytes from cell death. Its high expression in human melanoma cells and tumors suggests a similar role in malignant cells as well. The differential release and suppression of E2F transcriptional activity is likely to depend on promoter-specific E2F/Rb interaction. Phosphorylated Rb is displaced from cell cycle genes but not from others. In addition, Rb gene repression is dependent on the nature of Rb-E2F interaction and the activity of the Rb-bound proteins recruited to the promoter. Deciphering the differences in Rb/E2F complex formation in normal and malignant melanocytes is likely to shed light on the mechanism by which Rb can exert tumor suppressing and promoting activities in this cellular system. The Rb/E2F pathway provides opportunities for efficient therapy at multiple levels. Novel drugs can reactivate Rb potential to suppress growth cycle promoting genes. In addition, the high E2F transcriptional activity in melanoma cells can be exploited to deliver cytotoxic molecules specifically to tumors, sparing the normal tissues.

RBP2‐H1/JARID1B is a transcriptional regulator with a tumor suppressive potential in melanoma cells

“…4 Interestingly, pRb has been reported to bind also other chromatin remodeling factors, such as histone deacetylase, H3 methyl-transferase and members of the chromatin remodeling complex SWI/ SNE, suggesting that pRb together with JARID1B represents a multimolecular scaffold involved in chromatin modification. 67 Performing a series of functional assays, we could confirm the apoptotic and antiproliferative potential of re-expressed full-length RBP2-H1 that was predicted by our genome-wide expression analysis. However, our experiments also suggested that re-establishment of RBP2-H1 may induce apoptosis only in a minor percentage of transfected melanoma cells and that, after this initial spike in apoptosis, remaining cells undergo cell cycle arrest and enhanced proliferation control later on.…”

ARF functions as a melanoma tumor suppressor by inducing p53-independent senescence

“…These data demonstrate that Arf down-regulates melanocyte E2F1 levels through a proteasomal-degradation mechanism that could account, at least in part, for its ability to trigger melanocyte growth arrest. Importantly, E2F activity has been associated with senescence in mouse and human melanocytes and has been implicated in human melanoma (24)(25)(26). However, because Arf has many binding partners and other activities (4), additional mechanisms may be involved in Arf-mediated senescence.…”

Simultaneous Knockdown of Mutant BRAF and Expression of INK4A in Melanoma Cells Leads to Potent Growth Inhibition and Apoptosis

“…10B). Phosphorylation of S780, S795, and S807/811 of RB, known cyclin D:CDK4 and cyclin E:CDK2 targets (Halaban, 2005), is decreased in cells treated with either PD98059 or 219476 (except S780 and S807/811 in OM431 cells), and further reduced in cells with combinatorial treatment (Fig. 10C).…”

“…It has been well-established that constitutive activation of the ERK signaling induces the expression of cyclin D (Michaloglou et al, 2008;Rotolo et al, 2005), which binds to and activates CDK4 leading to the phosphorylation of RB protein facilitating cell cycle entry (Halaban, 2005). Consistent with an epistatic regulation between ERK pathway and cyclin D:CDK4, amplification of cyclin D1 and CDK4 genes have been identified mainly in melanomas that harbor wild-type NRAS and BRAF (Curtin et al, 2005;Smalley et al, 2008).…”