Transformation of hematopoietic cells by the Ski oncoprotein involves repression of retinoic acid receptor signaling

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, RAR␣. 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 receptorinduced 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 RAR␣-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.

Inhibition of retinoic acid receptor signaling by Ski in acute myeloid leukemia

“…[9][10][11] Because Dahl et al 12 showed that Ski could be involved in the repression of RAR signaling and we found a lower SKI expression in the more differentiated AML subgroups (e.g. t(15;17)), we decided to further investigate Ski and its interference with the RARa signaling pathway in AML.…”

Ski can negatively regulates macrophage differentiation through its interaction with PU.1

“…Recently, we and others reported that Ski expression is highly upregulated in bone marrow samples from patients with monosomy 7 or deletion 7q acute myeloid leukemia (AML) and CD34 þ cells from patients with chronic myelogenous leukemia (CML) (Kronenwett et al, 2005;Ritter et al, 2006). The effect of Ski on PU.1 might render Ski a more potent inhibitor of cell differentiation in cooperation with its known repression activity in retinoic acid signaling in myeloid cells (Dahl et al, 1998;Ritter et al, 2006).…”

“…His-tagged PU.1 and GST or GST-Ski were co-expressed in DH5a host strain and purified as described (Dahl et al, 1998). For each copurification, bacterial lysate containing 1 mg of GST fusion protein was applied to Glutathione Sepharose 4B (GE Healthcare), washed extensively in phosphate-buffered saline (PBS) containing 0.5% Triton X-100.…”

“…Analyses of human tumors have accumulated evidence that Ski is overexpressed in certain types of tumors such as leukemias, melanomas and esophageal carcinomas (Reed et al, 2001;Fukuchi et al, 2004;Kronenwett et al, 2005;Ritter et al, 2006). Ski has been also shown to influence the growth and differentiation of hematopoietic cells (Larsen et al, 1992(Larsen et al, , 1993Beug et al, 1995;Dahl et al, 1998). These previous studies demonstrated that Ski could transform hematopoietic multipotent progenitors and cause highly malignant leukemia.…”

“…Ski has been shown to be involved in certain distinct signaling pathways including nuclear receptors (Dahl et al, 1998;Nomura et al, 1999;Ueki and Hayman, 2003b;Ritter et al, 2006), transforming growth factor-b (TGF-b) (Akiyoshi et al, 1999;Luo et al, 1999;Sun et al, 1999;Xu et al, 2000;Ueki and Hayman, 2003a) and tumor suppressors Tokitou et al, 1999;Khan et al, 2001) where Ski can act as a transcriptional corepressor. This is in part due to its direct and indirect interactions with histone deacetylase (HDAC) complexes including nuclear receptor-corepressor/silencing mediator for retinoid and thyroid hormone receptors (N-CoR/SMRT) and Sin3A corepressors Jepsen and Rosenfeld, 2002).…”