Critical role of CDK2 for melanoma growth linked to its melanocyte-specific transcriptional regulation by MITF

Du, Jinyan; Widlund, Hans R.; Horstmann, Martin; Ramaswamy, Sridhar; Ross, Ken N.; Huber, Wade E.; Nishimura, Emi K.; Golub, Todd R.; Fisher, David E.

doi:10.1016/j.ccr.2004.10.014

Cited by 365 publications

(324 citation statements)

References 30 publications

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“…MITF's control of melanoma cell proliferation has been previously explained by its activation of various genes that are involved in cell growth, such as TBX2, CDK2, and BIRC7 (16)(17)(18). Importantly, forced expression of BPTF cDNA rescued the inhibition of melanoma colony formation caused by MITF depletion, suggesting that MITF directs its prosurvival program in the melanocytic lineage, at least in part, by activating BPTF expression.…”

Section: Discussionmentioning

confidence: 94%

BPTF transduces MITF-driven prosurvival signals in melanoma cells

Dar

Majid

Bezrookove

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Microphthalmia-associated transcription factor (MITF) plays a critical and complex role in melanocyte transformation. Although several downstream targets of MITF action have been identified, the precise mechanisms by which MITF promotes melanocytic tumor progression are incompletely understood. Recent studies identified an oncogenic role for the bromodomain plant homeodomain finger transcription factor (BPTF) gene in melanoma progression, in part through activation of BCL2, a canonical target of MITF signaling. Analysis of the BPTF promoter identified a putative MITF-binding site, suggesting that MITF may regulate BPTF expression. Overexpression of MITF resulted in up-regulation of BPTF in a panel of melanoma and melanocyte cell lines. shRNA-mediated down-regulation of MITF in melanoma cells was accompanied by down-regulation of BPTF and BPTF-regulated genes (including BCL2) and resulted in reduced proliferative capacity of melanoma cells. The suppression of cell growth mediated by MITF silencing was rescued by overexpression of BPTF cDNA. Binding of MITF to the BPTF promoter was demonstrated using ChIP analysis. MITF overexpression resulted in direct transcriptional activation of BPTF, as evidenced by increased luciferase activity driven by the BPTF promoter. These results indicate that BPTF transduces key prosurvival signals driven by MITF, further supporting its important role in promoting melanoma cell survival and progression. melanoma | signaling cascade | oncogenes M icrophthalmia-associated transcription factor (MITF) is known to play a key role in melanocyte biology and progression. MITF performs these functions by activating transcription of many genes through interaction with the consensus DNA-binding sequence (CACGTG, termed E box) present on the promoters of target genes. MITF controls expression of several proteins required for melanin synthesis, including tyrosinase (TYR), tyrosinase-related protein 1 (TYRP1), and dopachrome tautomerose (DCT) (1-3). In addition, MITF plays a critical role in melanocyte survival and serves as a lineagespecific oncogene in melanoma, as evidenced by its amplification in a subset of melanomas (4-6). MITF expression is regulated by several factors, including SOX-10, CREB, PAX3, LEF1, and ATF2 (7,8). MITF in turn regulates a plethora of genes, with its complex role in melanoma biology, as its overexpression has been shown to result in both proproliferative and antiproliferative stimuli (4, 5, 9, 10). Accordingly, verified targets of MITF include both genes that promote cell survival and block apoptosis, (e.g., CDK2, BCL2, DIAPH1, and TBX2), and genes that block cell cycle progression (e.g., CDKN2A and p21Cip1). Thus, although several downstream targets of MITF action have been identified, the precise mechanisms by which MITF promotes melanocytic tumor progression are still poorly understood.Recently, we identified a role for the bromodomain plant homeodomain finger transcription factor (BPTF) gene in melanoma progression (11). BPTF is the largest subunit of the nucleoso...

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Section: Discussionmentioning

confidence: 94%

BPTF transduces MITF-driven prosurvival signals in melanoma cells

Dar

Majid

Bezrookove

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Indeed, unopposed activation of CDK2 as well as CDK4/6 mediates hyperphosphorylation of all Rb pocket proteins in melanoma (Halaban 1999). CDK2 inhibition, in particular, may offer a theoretical therapeutic index in melanoma, because melanoma cell lines appeared to exhibit particular dependence on this kinase, whereas normal tissues (and nonmelanoma cancers) appeared to tolerate CDK2 inhibition (Tetsu and McCormick 2003;Du et al 2004). These findings have prompted the clinical development of several agents capable of inhibiting CDKs.…”

Section: Cyclin-dependent Kinasesmentioning

confidence: 99%

Malignant melanoma: genetics and therapeutics in the genomic era

2006

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Cell for cell, probably no human cancer is as aggressive as melanoma. It is among a handful of cancers whose dimensions are reported in millimeters. Tumor thickness approaching 4 mm presents a high risk of metastasis, and a diagnosis of metastatic melanoma carries with it an abysmal median survival of 6-9 mo. What features of this malignancy account for such aggressive behavior? Is it the migratory history of its cell of origin or the programmed adaptation of its differentiated progeny to environmental stress, particularly ultraviolet radiation? While the answers to these questions are far from complete, major strides have been made in our understanding of the cellular, molecular, and genetic underpinnings of melanoma. More importantly, these discoveries carry profound implications for the development of therapies focused directly at the molecular engines driving melanoma, suggesting that we may have reached the brink of an unprecedented opportunity to translate basic science into clinical advances. In this review, we attempt to summarize our current understanding of the genetics and biology of this disease, drawing from expanding genomic information and lessons from development and genetically engineered mouse models. In addition, we look forward toward how these new insights will impact on therapeutic options for metastatic melanoma in the near future. The diseaseMelanomas most often arise within epidermal melanocytes of the skin, although they can also derive from noncutaneous melanocytes such as those lining the choroidal layer of the eye, GI and GU mucosal surfaces, or the meninges. Melanoma is also among the more common causes of "metastatic cancer of unknown primary," which may reflect either a propensity to arise in unexpected sites along the neural crest migratory route, or rapid growth of poorly differentiated lesions arising from indolent or unrecognized cutaneous primary lesions. Clinical staging for primary cutaneous melanoma employs measurements of thickness (in millimeters), presence of ulceration, penetration through cutaneous layers, mitotic rate, evidence of "in transit" metastasis, tumor spread to draining lymph nodes, and evidence of distant metastasis. Management issues in melanoma can be classified in terms of prevention, diagnosis, local disease management, and treatment of metastatic disease.In view of the epidemiological and emerging experimental evidence linking melanoma incidence to UV exposure and skin phototype, prevention and screening strategies represent key areas for reduction of disease incidence and severity. For most cutaneous melanomas in the so-called radial growth phase (e.g., thin melanomas), surgical removal affords curative treatment. In contrast, a significant fraction of patients diagnosed with intermediate-thickness (2-4 mm) cutaneous melanoma eventually succumb to recurrence at regional or distant sites.Critical biological questions facing the melanoma research community include: (1) What genetic and environmental factors contribute to and/or modulate risk of melanom...

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“…By transfecting dominantnegative (DN) mutant of Mitf into melanoma, McGill et al 25 demonstrated that Mitf upregulates Bcl2 and blocks apoptosis of the tumor cell. Du et al 26 showed that suppression of Mitf inhibits CDK2 expression, leading to cell cycle arrest and growth inhibition. Garraway et al 27 documented that Mitf may be involved in malignant transformation of melanocytes and survival of melanoma in cooperation with BRAF, while DN Mitf renders melanoma cells susceptible to chemotherapeutic agents.…”

Section: Introductionmentioning

confidence: 99%

Therapeutic RNA interference of malignant melanoma by electrotransfer of small interfering RNA targeting Mitf

et al. 2006

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Microphthalmia-associated transcription factor (Mitf) is critically involved in melanin synthesis as well as differentiation of cells of the melanocytic lineage. Some earlier studies suggested that Mitf is also essential in the survival of melanoma cells, but this notion remains controversial. We synthesized short interfering RNA (siRNA) duplexes corresponding to the mitf sequence and transfected them into B16 melanoma. Lipid-mediated transfection in vitro of Mitfspecific siRNA resulted in specific downregulation of Mitf and of the tyrosinase that is a transcriptional target of Mitf. This treatment also remarkably reduced the viability of melanoma cells by inducing apoptosis. To examine the potential feasibility of RNAi therapy against melanoma, B16 cells were subcutaneously injected into syngenic mice and siRNA was transfected into the pre-established tumor by means of electroporation. The Mitf-specific siRNA drastically reduced outgrowth of subcutaneous melanoma, while nonspecific siRNA failed to affect tumor progression. Terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling-based analysis of tumor specimens demonstrated that the tumor cells transfected with Mitf-siRNA effectively underwent apoptosis in vivo. The present results indicate that Mitf plays important roles in melanoma survival. Intratumor electrotransfer of Mitf-specific siRNA may provide a powerful strategy for therapeutic intervention of malignant melanoma.

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Critical role of CDK2 for melanoma growth linked to its melanocyte-specific transcriptional regulation by MITF

Cited by 365 publications

References 30 publications

BPTF transduces MITF-driven prosurvival signals in melanoma cells

BPTF transduces MITF-driven prosurvival signals in melanoma cells

Malignant melanoma: genetics and therapeutics in the genomic era

Therapeutic RNA interference of malignant melanoma by electrotransfer of small interfering RNA targeting Mitf

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