The incidence of melanoma is increasing at one of the highest rates of any form of cancer in the United States, with the current lifetime risk being one in 68. At present, there are limited systemic therapies to treat advanced stages of melanoma, and the key to improved survival remains early detection. Recent discoveries have allowed for a clearer picture of the molecular events leading to melanoma development and progression. Since identifying prevalent activating mutations of the BRAF kinase in melanomas, there has been a flood of additional molecular studies to further clarify the role of this pathway and others in melanomagenesis. In particular, recent genetic studies have demonstrated specific genotype-phenotype correlations that provide the first major insights into the molecular subclassification of melanoma and the heterogeneous nature of this malignancy. In this article, we review the most up-to-date molecular discoveries in melanoma biology and provide a framework for understanding their significance in melanoma development and progression. We also provide details on the development of novel therapies based on these recent molecular discoveries and insight into current and planned clinical trials. It is expected that these latest studies in melanoma will help define the critical molecular events involved in disease onset and progression and allow us to move rapidly toward a true molecular classification. We eagerly anticipate rationally designed melanoma therapies based on such a classification scheme and the associated improvements in patient outcomes.
The Id family of helix-loop-helix transcription factors is upregulated in a variety of human malignancies and has been implicated in promoting tumorigenesis through effects on cell growth, differentiation, and tumor angiogenesis. While expression of Id proteins has been associated with tumorigenesis, the precise mechanistic relationship between Id expression and carcinogenesis has not been clearly delineated. We have previously shown that Id1 delays cellular senescence in primary mammalian cells through inhibition of the cell cycle regulatory protein and familial melanoma gene, p16/INK4a. We have also demonstrated that Id1 expression is upregulated in early stage primary human melanomas and may be an important marker for early malignancy. In order to further define the role of Id1 in human melanoma development, we have evaluated the function of Id1 in primary human melanocytes. Here we show that constitutive expression of Id1 in primary human melanocytes leads to delayed cellular senescence and decreased expression of the familial melanoma gene, p16/INK4a. Although melanocytes constitutively expressing Id1 are shown to possess extended lifespans, this is not associated with an appreciable change in cell growth or telomere length. We conclude that Id1 delays cellular senescence in primary human melanocytes through inhibition of p16/INK4a expression and suggest that Id1 may contribute to the malignant conversion of primary human melanocytes through extension of cellular lifespan.
WNKs (with‐no‐lysine [K]) 1–4 are unique protein‐serine/threonine kinases conserved in multicellular organisms. The ATP‐binding lysine present in all protein kinases is in an atypical position in WNKs. Two of the four WNKs were identified as genes mutated in pseudohypoaldosteronism type II, a genetic syndrome characterized by hypertension and hyperkalemia. All four WNKs contain very large noncatalytic regions with no currently known domain organization that appear to function as scaffolds. WNKs have been implicated not only in regulation of ion balance, but also in cell survival and proliferation, membrane trafficking and embryonic organ development. Mitogen‐activated protein kinases MAPKs transduce signals in a multitude of cellular pathways in response to many ligands and cell stimuli. MAPKs have been implicated in diseases including cancer, inflammatory disease, obesity, and diabetes. The MAPKs ERK1/2 are required for glucose‐regulated insulin gene transcription in pancreatic beta cells. Nutrients and hormones that stimulate or reduce insulin secretion have a parallel effect on ERK1/2 activity in beta cells. ERK1/2 control the function of several transcription factors that mediate glucose‐regulated insulin gene transcription, including at least two factors that are encoded by maturity‐onset diabetes (MODY) genes.Research supported by grants from the National Institutes of Health, R01‐GM53032, R37‐DK034128, R01‐DK055310 and the Robert A. Welch Foundation I‐1243 and the American Diabetes Association Mentor‐based Postdoctoral Fellowship award.
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