Cytoplasmic localization of the oncogenic protein ski in human cutaneous melanomas in vivo: Functional implications for transforming growth factor beta signaling

The oncogenic protein Ski associates with Smad proteins and counter acts th eir activation of gene expression and growth inhibition in response to tran sforming growth factor beta (TGF-beta). Here we show that Ski protein level s are increased in all 44 human melanoma tumor tissues analyzed in vivo In addition, Ski subcellular localization changes from nuclear, in preinvasive melanomas (melanomas in situ), to nuclear and cytoplasmic in primary invas ive and metastatic melanomas. Furthermore, Ski/Smad association in the cyto plasm seems to prevent Smad3 nuclear translocation in response to TGF-beta. The biological significance of Ski overexpression in melanomas was establi shed by showing that down-regulation of Ski levels by antisense Ski vectors , restored TGF-beta -mediated growth inhibition Such inhibition is apparent ly mediated by up-regulation of the cyclin dependent kinase-I p21(Waf-1) an d inhibition of cyclin-dependent kinase activity. Our results suggest that high levels of Ski in human melanoma produce a disruption of TGF-beta signa ling phenotypically similar to that I cells harboring mutations in TGF-beta receptors or Smad proteins, and this may represent a significant event in the progression of melanomas in vivo.