Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0278883 (metastatic melanoma)
 6,224 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The proteins SKI and SnoN are implicated in processes as diverse as differentiation, transformation and tumor progression. Until recently, SKI was solely viewed as a nuclear protein with a principal function of inhibiting TGF-beta signaling through its association with the Smad proteins. However, new studies suggest that SKI plays additional roles not only inside but also outside the nucleus. In normal melanocytes and primary non-invasive melanomas, SKI localizes predominantly in the nucleus, whereas in primary invasive melanomas SKI displays both nuclear and cytoplasmic localization. Intriguingly, metastatic melanoma tumors display nuclear and cytoplasmic or predominantly cytoplasmic SKI distribution. Cytoplasmic SKI is functional, as it associates with Smad3 and prevents its nuclear localization mediated by TGF-beta. SKI can also function as a transcriptional activator, targeting the beta -catenin pathway and activating MITF and NrCAM, two proteins involved in survival, migration and invasion. Intriguingly, SKI appears to live a dual life, one as a tumor suppressor and another as a transforming protein. Loss of one copy of mouse ski increases susceptibility to tumorigenesis in mice, whereas its overexpression is associated with cancer progression of human melanoma, esophageal, breast and colon. The molecular reasons for such dramatic change in SKI function appear to result from new acquired activities. In this review, we discuss the mechanisms by which SKI regulates crucial pathways involved in the progression of human malignant melanoma.
 ...
PMID:SKI pathways inducing progression of human melanoma. 1598 36

Src signaling has been implicated in several malignancies including melanoma. The prevalence of Src activation in human melanoma and the effect of the newer Src inhibitors, dasatinib, and bosutinib (SKI-606), as single agents or in combination, on melanoma cell lines is not well established. In the melanoma cell lines, A-375, SK-Mel-5, and SK-Mel-28, activity of Src inhibitors was assessed alone or in combination with standard chemotherapy agents; 50% growth inhibitory concentration was determined by MTS assay and immunoblotting was used to measure Src activation and downstream signaling. Staining for Src activation was measured by Src-phosphotyrosine 416. Immunohistochemistry was performed on primary cutaneous, mucosal, and metastatic melanoma. Src inhibitors blocked the growth of melanoma cell lines; furthermore, Src inhibitor treatment was synergized with cisplatin but not temozolomide or paclitaxel. Treatment with dasatanib increased the levels of pS473 Akt in A-375 melanoma cells but not in the other two cell lines. Forty-eight percent (17 of 35) of all melanoma stained weakly, moderately, or strongly for pY416 Src: cutaneous 61% (eight of 13), mucosal 31% (four of 13), metastatic 55% (five of nine). Most positive biopsies stained weakly and only one metastatic melanoma specimen stained strongly for Src-phosphotyrosine 416. pY416 Src is expressed in cutaneous, mucosal, and metastatic melanoma in various degrees. Src inhibitors may be a promising therapy in melanoma, either by themselves or in combination with chemotherapy (especially with platinum compounds) or inhibitors of the Akt/PI3k pathway.
 ...
PMID:Src activation in melanoma and Src inhibitors as therapeutic agents in melanoma. 1943 4