Mitf cooperates with Rb1 and activates p21Cip1 expression to regulate cell cycle progression

Abstract

The controls that enable melanoblasts and melanoma cells to proliferate are likely to be related, but so far no key regulator of cell cycle progression specific to the melanocyte lineage has been identified. The microphthalmia-associated transcription factor Mitf has a crucial but poorly defined role in melanoblast and melanocyte survival and in differentiation. Here we show that Mitf can act as a novel anti-proliferative transcription factor able to induce a G1 cell-cycle arrest that is dependent on Mitf-mediated activation of the p21(Cip1) (CDKN1A) cyclin-dependent kinase inhibitor gene. Moreover, cooperation between Mitf and the retinoblastoma protein Rb1 potentiates the ability of Mitf to activate transcription. The results indicate that Mitf-mediated activation of p21Cip1 expression and consequent hypophosphorylation of Rb1 will contribute to cell cycle exit and activation of the differentiation programme. The mutation of genes associated with melanoma, such as INK4a or BRAF that would affect either Mitf cooperation with Rb1 or Mitf stability respectively, would impair Mitf-mediated cell cycle control.

Aberrant miR-182 expression promotes melanoma metastasis by repressing FOXO3 and microphthalmia-associated transcription factor

“…However, direct measurements of MITF during melanoma progression by ourselves and others (23)(24)(25) suggest that MITF is more commonly down-regulated in advanced melanoma. In addition to its role in differentiation, MITF represses cell proliferation by activating the expression of cell-cycle inhibitors, such as p16 INK4a (26) and p21 Cip1 (27). Furthermore, MITF has been directly linked to the control of cell migration by regulating DIA1, which coordinates the actin cytoskeleton and microtubule networks at the cell periphery (28).…”

β-Catenin induces immortalization of melanocytes by suppressing p16INK4a expression and cooperates with N-Ras in melanoma development

“…Recent evidence has revealed that low levels of Mitf activity can promote proliferation (Carreira et al 2006) while high levels inhibit cell division (Carreira et al 2005;Loercher et al 2005;Wellbrock and Marais 2005). Since ␤-catenin can directly activate the Mitf-M promoter via a LEF/Tcf-binding site (Takeda et al 2000), any activation of ␤-catenin would either promote or inhibit proliferation depending on the basal level of Mitf activity in the cell.…”

“…Even though it is not formally proven, it is more likely that the in vivo proliferation of melanoblasts was impaired by the production of bcat sta during melanocyte development. We showed previously that Mitf-M represses proliferation in melanoma cells (Carreira et al 2005). Mitf-M was induced in E13.5 transgenic melanoblasts and was thus more abundant than in wild-type melanoblasts ( Supplementary Fig.…”

Malignant melanoma: genetics and therapeutics in the genomic era

“…These designations undoubtedly represent some degree of oversimplification, yet may be helpful in linking Mitf biochemistry to major pathways with which it is associated. Two interesting reported transcriptional targets are the cyCDK inhibitors (CDKi) INK4A (Loercher et al 2005) and p21 (Carreira et al 2005). Both potentially provide links to melanocytic differentiation although neither alone is apparently essential for melanocyte differentiation/pigmentation, since knockouts of both appear normally pigmented.…”