Characterization of Sno expression in malignant melanoma.
Normal cells are controlled by several exocrine factors, whereas tumor cells often lose control by antiproliferative stimuli. It is known that melanoma cells produce transforming growth factor (TGF) beta1, 2 and 3, but do not respond with growth inhibition. Recently, the Smad inhibitor Ski was found to play a role in this process. We originally analyzed Ski expression in nine melanoma cell lines, however, only one cell line (SK Mel 28) was positive. As all nine cell lines were unresponsive to TGF-beta, we continued to search for the responsible mechanism. Sequencing of the TGF-beta-receptor II, known to be mutated in other kinds of cancer, did not reveal any mutation. A family member of Ski, the proto-oncogene Sno was strongly expressed in all melanoma cell lines on RNA and protein level, but not in melanocytes. To confirm functional relevance of this observation, we used stable antisense Sno transfection for the generation of cell clones with reduced Sno expression. These cell clones displayed reduced cell proliferation, indicating participation of Sno in the escape of melanoma cells from TGF-beta dependent growth control. Searching for TGF-beta target genes that are under control of Sno interference, Id1 but not antiproliferative genes p21, p15, p57 and p27 was identified in the cell clones after antisense Sno expression. In summary, constitutive Sno expression was identified as an important mechanism to shut off antiproliferative TGF-beta signaling in malignant melanoma.
Poser
Ina
I
University of Regensburg Medical School, D-93053 Regensburg, Germany.
Rothhammer
Tanja
T
Dooley
Steven
S
Weiskirchen
Ralf
R
Bosserhoff
Anja-Katrin
AK
D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008545:Melanoma / Q000235:genetics* / Q000473:pathology*; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D012878:Skin Neoplasms / Q000235:genetics* / Q000473:pathology*; D014157:Transcription Factors; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D047908:Intracellular Signaling Peptides and Proteins; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; C060615:SKIL protein, human; D014157:Transcription Factors; D016212:Transforming Growth Factor beta