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

• Published in: Cancer research (Chicago, Ill.) Ill.), 2001-11, Vol.61 (22), p.8074-8078
• Main Authors: REED, Jon A, BALES, Elise, WEIDONG XU, OKAN, Nihal A, BANDYOPADHYAY, Debdutta, MEDRANO, Estela E
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Cell Division - physiology; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cytoplasm - metabolism; Dermatology; DNA-Binding Proteins - biosynthesis; DNA-Binding Proteins - metabolism; Fundamental and applied biological sciences. Psychology; Humans; Medical sciences; Melanoma - metabolism; Melanoma - pathology; Molecular and cellular biology; Proto-Oncogene Proteins - biosynthesis; Proto-Oncogene Proteins - metabolism; Signal Transduction - physiology; Skin Neoplasms - metabolism; Skin Neoplasms - pathology; Smad3 Protein; Trans-Activators - metabolism; Transforming Growth Factor beta - physiology; Tumor Cells, Cultured; Tumors of the skin and soft tissue. Premalignant lesions
• ISSN: 0008-5472; 1538-7445

The oncogenic protein Ski associates with Smad proteins and counteracts their activation of gene expression and growth inhibition in response to transforming growth factor beta (TGF-beta). Here we show that Ski protein levels 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 invasive and metastatic melanomas. Furthermore, Ski/Smad association in the cytoplasm seems to prevent Smad3 nuclear translocation in response to TGF-beta. The biological significance of Ski overexpression in melanomas was established by showing that down-regulation of Ski levels, by antisense Ski vectors, restored TGF-beta-mediated growth inhibition. Such inhibition is apparently mediated by up-regulation of the cyclin-dependent kinase-I p21(Waf-1) and inhibition of cyclin-dependent kinase 2 activity. Our results suggest that high levels of Ski in human melanomas produce a disruption of TGF-beta signaling phenotypically similar to that in cells harboring mutations in TGF-beta receptors or Smad proteins, and this may represent a significant event in the progression of melanomas in vivo.