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

Abstract

Acute myeloid leukemia (AML) is a heterogeneous disease with multiple different cytogenetic and molecular aberrations contributing to leukemic transformation. We compared gene expression profiles of 4608 genes using cDNA-arrays from 20 AML patients (nine with À7/del7q and 11 with normal karyotype) with 23 CD34 þ preparations from healthy bone marrow donors. SKI, a nuclear oncogene, was highly up regulated. In a second set of 183 AML patients analyzed with real-time PCR, the highest expression level of SKI in AML with À7/del7q could be confirmed. As previously described, Ski associates with the retinoic acid receptor (RAR) complex and can repress transcription. We wanted to investigate the interference of Ski with RARa signaling in AML. Ski was co-immunoprecipitated and colocalized with RARa. We also found that overexpression of wild-type Ski inhibited the prodifferentiating effects of retinoic acid in U937 leukemia cells. Mutant Ski, lacking the N-CoR binding, was no more capable of repressing RARa signaling. The inhibition by wild-type Ski could partially be reverted by the histone deacetylase blocking agent valproic acid. In conclusion, Ski seems to be involved in the blocking of differentiation in AML via inhibition of RARa signaling.

Transforming Growth Factor-β Suppresses the Ability of Ski to Inhibit Tumor Metastasis by Inducing Its Degradation

“…The oncogenic activity of Ski is primarily defined by its ability to promote anchorage-independent growth of chicken and quail embryo fibroblast when overexpressed (3). Consistent with this, Ski has been found to be expressed at high levels in human cancer cells derived from melanoma, esophageal cancer, colorectal cancer, pancreatic cancer, and leukemia (4)(5)(6)(7)(8). However, Ski may also contain an antitumorigenic activity.…”

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

“…Given that Ski can strongly influence the biological role of PU.1, Ski might also be involved in the cell fate determination and leukemogenesis. 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).…”

“…Previous studies identified a point mutation in Ski (L110P) which severely affects its interaction with N-CoR, Smad2/3 and GATA1, but not with Sin3A, Smad4, retinoic acid receptor and vitamin D receptor (Ueki and Hayman, 2003a, b;Ueki et al, 2004;Ritter et al, 2006). This mutation substantially affects the repression activity of Ski on nuclear receptors and GATA1 but not TGF-b signaling.…”

“…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).…”

“…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).…”