SKI Oncoprotein

Abstract: The bone morphogenic proteins (BMPs) play important roles in vertebrate development. In Xenopus, BMPs act as epidermal inducers and also as negative regulators of neurogenesis. Antagonism of BMP signaling results in neuralization. BMPs signal through the cell-surface receptors and downstream Smad molecules. Upon stimulation with BMP, Smad1, Smad5, and Smad8 are phosphorylated by the activated BMP receptors, form a complex with Smad4, and translocate into the nucleus, where they regulate the expression of BMP target genes. Here, we show that the Ski oncoprotein can block BMP signaling and the expression of BMP-responsive genes in both Xenopus and mammalian cells by directly interacting with and repressing the activity of BMP-specific Smad complexes. This ability to antagonize BMP signaling results in neuralization by Ski in the Xenopus embryo and blocking of osteoblast differentiation of murine W-20-17 cells. Thus, Ski is able to repress the activity of all receptor-associated Smads and may regulate vertebrate development by modulating the signaling activity of transforming growth factor-β family members.

Abstract: The v-ski oncogene is a truncated version of the cellular proto-oncogene, c-ski, and lacks sequences coding for both the N- and C-terminal ends of the c-ski protein. In the region of overlap, v-ski and c-ski differ by only one amino acid. To determine whether these differences underlie v-ski's oncogenic activation, we have cloned cDNAs for several alternatively spliced c-ski mRNAs and introduced these cDNAs into replication-competent retroviral vectors. The biological activities of these c-ski constructs have been compared with those of v-ski. We found that all c-ski gene products, when expressed at high levels from the promoter in the retroviral long terminal repeat, can induce morphological transformation, anchorage independence, and muscle differentiation in avian cells. Cells that are susceptible to ski-induced transformation and myogenesis normally express endogenous c-ski at low levels. Thus, it appears that overexpression of ski is sufficient for oncogenic and myogenic activation.

Abstract: The Ski oncogene has dramatic effects on the differentiation of several different cell types. It induces the differentiation of quail embryo cells into myoblasts and arrests the differentiation of chicken hematopoietic cells. The mechanism that Ski uses to carry out these disparate biological activities is unknown. However, we were struck by the similarity of these effects to those of certain members of the nuclear hormone receptor family. Both Ski and the thyroid hormone receptor-derived oncogene v-ErbA can arrest the differentiation of avian erythroblasts, and v-Ski-transformed avian multipotent progenitor cells resemble murine hematopoietic cells that express a dominant-negative form of the retinoic acid receptor, RARα. In this paper, we have tested the hypothesis that v-Ski and its cellular homologue c-Ski exert their effects by interfering with nuclear hormone receptor-induced transcription. We demonstrate that Ski associates with the RAR complex and can repress transcription from a retinoic acid response element. The physiological significance of this finding is demonstrated by the ability of high concentrations of a RARα-specific ligand to abolish v-Ski-induced transformation of the multipotent progenitors. These results strongly suggest that the ability of Ski to alter cell differentiation is caused in part by the modulation of RAR signaling pathways.