ABSTRACT
The
family of cyclin D proteins plays a crucial role in the early events of
the mammalian cell cycle. Recent studies have revealed the involvement
of AML1 transactivation activity in promoting cell cycle progression
through the induction of cyclin D proteins. This information in
combination with our previous observation that a region in AML1 between
amino acids 213 and 289 is important for its function led us to
investigate prospective proteins associating with this region. We
identified cyclin D3 by a yeast two-hybrid screen and detected AML1
interaction with the cyclin D family by both in vitro pull-down and in
vivo coimmunoprecipitation assays. Furthermore, we demonstrate that
cyclin D3 negatively regulates the transactivation activity of AML1 in
a dose-dependent manner by competing with CBFβ for AML1
association, leading to a decreased binding affinity of AML1 for its
target DNA sequence. AML1 and its fusion protein AML1-ETO have been shown to shorten and prolong the mammalian cell cycle,
respectively. In addition, AML1 promotes myeloid cell differentiation.
Thus, our observations suggest that the direct association of cyclin D3
with AML1 functions as a putative feedback mechanism to regulate cell
cycle progression and
differentiation.
Regulation of mammalian cell cycle progression in the regenerating liver