Abstract
The Ski and Sno oncoproteins are components of a macromolecular complex containing the co-repressor N-CoR/SMRT, mSin3 and histone deacetylase. This complex has been implicated in the transcriptional repression exerted by a number of repressors including nuclear hormone receptors and Mad. Further more, Ski and Sno negatively regulate transforming growth factor-β (TGF-β) signaling by recruiting this complex to Smads. Here we show that loss of one copy of
sno
increases susceptibility to tumorigenesis in mice. Mice lacking
sno
died at an early stage of embryogenesis, and
sno
was required for blastocyst formation. Heterozygous (
sno
+/–
) mice developed spontaneous lymphomas at a low frequency and showed an increased level of tumor formation relative to wild-type mice when challenged with a chemical carcinogen.
sno
+/–
embryonic fibroblasts had an increased proliferative capacity and the introduction of activated Ki-
ras
into these cells resulted in neoplastic transformation. The B cells, T cells and embryonic fibroblasts of
sno
+/–
mice had a decreased sensitivity to apoptosis or cell cycle arrest. These findings demonstrate that
sno
acts as a tumor suppressor at least in some types of cells.
