The Ski oncoprotein dramatically affects cell growth, differentiation, and/or 
survival. Recently, Ski was shown to act in distinct signaling pathways 
including those involving nuclear receptors, transforming growth factor beta, 
and tumor suppressors. These divergent roles of Ski are probably dependent on 
Ski's capacity to bind multiple partners with disparate functions. In 
particular, Ski alters the growth and differentiation program of erythroid 
progenitor cells, leading to malignant leukemia. However, the mechanism 
underlying this important effect has remained elusive. Here we show that Ski 
interacts with GATA1, a transcription factor essential in erythropoiesis. Using 
a Ski mutant deficient in GATA1 binding, we show that this Ski-GATA1 interaction 
is critical for Ski's ability to repress GATA1-mediated transcription and block 
erythroid differentiation. Furthermore, the repression of GATA1-mediated 
transcription involves Ski's ability to block DNA binding of GATA1. This finding 
is in marked contrast to those in previous reports on the mechanism of 
repression by Ski, which have described a model involving the recruitment of 
corepressors into DNA-bound transcription complexes. We propose that Ski 
cooperates in the process of transformation in erythroid cells by interfering 
with GATA1 function, thereby contributing to erythroleukemia.