Transformation-defective v-ski induces MyoD and myogenin expression but not myotube formation.

Abstract

The ski oncogene induces muscle differentiation in otherwise nonmyogenic quail embryo cells (C. Colmenares and E. Stavnezer, Cell 59:293-303, 1989). Here we report that v-ski induces both MyoD and myogenin expression, suggesting that activation of these muscle regulatory genes may be a critical step in ski-induced myogenesis. We also describe a transformation-defective mutant of v-ski (tdM5i) that fails to induce myotube formation, although it induces the expression of many muscle-specific genes, including the MyoD and myogenin genes. Therefore, if activation of MyoD and myogenin expression is a necessary component of the myogenic program triggered by ski, it is clearly insufficient to account for complete muscle differentiation.

Interaction with Smad4 Is Indispensable for Suppression of BMP Signaling by c-Ski

“…The ARPG mutant of Ski protein was first described in v-Ski as a transformation-defective mutant (Colmenares et al, 1991). The ARPG mutation is an insertional mutation of four amino acids (Ala-Arg-Pro-Gly), replacing Asp in a po- et al, 1991).…”

“…In the model, c-Ski binds to L3 loop of Smad4, a loop that is responsible for interaction with R-Smads; thus, c-Ski inhibits formation of active Smad complex between R-Smads and Co-Smad. Although BMP-specific R-Smads bind to c-Ski only weakly (Akiyoshi et al, 1999;Mizuide et al, 2003), it has been shown that c-Ski inhibits BMP signaling in mammals and in Xenopus (Amaravadi et al, 1997;Wang et al, 2000).The ARPG mutant of Ski protein was first described in v-Ski as a transformation-defective mutant (Colmenares et al, 1991). The ARPG mutation is an insertional mutation of four amino acids (Ala-Arg-Pro-Gly), replacing Asp in a po- et al, 1991).…”

The Ski oncoprotein interacts with Skip, the human homolog of Drosophila Bx42

“…We have investigated whether Skip is this protein activity, but so far have not detected any DNA binding activity for Skip (data not shown). However Ski's interaction with Skip is still potentially very important since the minimal region identi®ed that mediates Ski interaction with Skip includes Ski sequence previously shown to be necessary for transformation (Colmenares et al, 1991b). This region is also very highly conserved sharing 75% identity over 107 amino acids between chicken Ski and Sno.…”

“…The coiled-coil domain has been shown to mediate homo-multimerization of Ski, and hetero-multimerization of Ski and the Ski related protein Sno (Heyman and Stavnezer, 1994;Nagase et al, 1993). By mutational analysis, the amphipathic helices have been shown to be required for Ski transformation of ®broblasts and induction of quail ®broblasts into myoblasts (Colmenares et al, 1991b).…”

“…This 107 amino acid segment was able to bind Skip (NCT1). Interestingly this region has been shown to be necessary for Ski's transforming ability (Colmenares et al, 1991b) and this region is highly conserved between Ski proteins and the Ski-related protein, Sno. As expected from this data fulllength chicken SnoN was also shown to interact with Skip in a two-hybrid assay (data not shown).…”