J Biol Chem. 2004 Jan 2;279(1):664-76. Epub 2003 Oct 10.
LEK1, a member of the LEK family of proteins, is ubiquitously expressed in developing murine tissues. Our current studies are aimed at identifying the role of LEK1 during cell growth and differentiation. Little is known about the function of LEK proteins. Recent studies in our laboratory have focused on the characterization of the LEK1 atypical Rb-binding domain that is conserved among all LEK proteins. Our findings suggest that LEK1 potentially functions as a universal regulator of pocket protein activity. Pocket proteins exhibit distinct expression patterns during development and function to regulate cell cycle, apoptosis, and tissue-specific gene expression. We show that LEK1 interacts with all three pocket proteins, p107, p130, and pRb. Additionally, this interaction occurs specifically between the LEK1 Rb-binding motif and the \"pocket domain\" of Rb proteins responsible for Rb association with other targets. Analyses of the effects of disruption of LEK1 protein expression by morpholino oligomers demonstrate that LEK1 depletion decreases cell proliferation, disrupts cell cycle progression, and induces apoptosis. Given its expression in developing cells, its association with pocket proteins, and its effects on proliferation, cell cycle, and viability of cells, we suggest that LEK1 functions in a similar manner to phosphorylation to disrupt association of Rb proteins with appropriate binding targets. Thus, the LEK1/Rb interaction serves to retain cells in a pre-differentiative, actively proliferative state despite the presence of Rb proteins during development. Our data suggest that LEK1 is unique among LEK family members in that it specifically functions during murine development to regulate the activity of Rb proteins during cell division and proliferation. Furthermore, we discuss the distinct possibility that a yet unidentified splice variant of the closely related human CENP-F, serves a similar function to LEK1 in humans.
Organism or Cell Type:
cell culture: mouse 3T3 fibroblasts and C2C12 myoblasts