Eukaryotic cell cycle progression is primarily controlled by a family of protein serine/threonine kinases, known as cyclin-dependent kinases (CDKs), that consist of an activating cyclin subunit and a catalytic subunit.  The principle negative regulation of CDKs is provided by two families of CDK inhibitors that link cell cycle control to such diverse processes as DNA repair, terminal differentiation, tumor suppression and cell senescence. Our current research combines genetic (knock-out mice) and biochemical approaches to determine the functions and transcriptional control of CDK inhibitor genes in tumor suppression and in stem and progenitor cell cycle control (Nature 366:701; Genes & Dev. 8:2939; Genes & Dev.12:2899; Genes & Dev.21:49).

Regulation of mammalian cell cycle by CDKs, cyclins and CDK inhibitors.
(A) Combinatorial interactions of CDK and cyclins promote the transition through the cell cycle. Two families of CDK inhibitors, INK4 ( p15 ^INK4b, p16^INK4a, p18^INK4c and p19^INK4d ) and p21 ( p21^CIP1/WAF1, p27^KIP1 and p57^KIP2), provide the major negative regulation of CDKs. The levels of both cyclins and the p21 family of inhibitors are regulated by ubiquitin-mediated proteolysis. The mechanism regulating INK4 levels is unknown at present. (B) Mice lacking CDK inhibitor gene p18INK4c exhibit a series of growth defects including gigantism as shown here. C) Multiple tumor types develop in mice lacking both CDK inhibitor gene p18^INK4c and p27^KIP1, demonstrating a functional collaboration between CDK inhibitor genes in suppressing tumor growth. The boxed area in the adrenal adenoma indicates an invasion of the medulla through the adrenal cortex.

The tumor suppressor p53 protein mediates cellular response to diverse insults by activating the transcription of various genes involved in either cell cycle arrest or apoptosis. An emerging regulatory step in p53-mediated tumor suppression is the function and regulation of p53 in the cytoplasm. Our current research in this area combines genetic and cellular approaches to determine how p53 contributes to mitochondrial-dependent apoptosis and is regulated by two closely related cytoplasmic E3 ubiquitin ligases (Cell 92:725; Mol. Cell 3:579; Science 292:1910).

Many cellular processes, including cell cycle progression, are controlled by proteolytic and non-proteolytic protein ubiquitination.  This process is catalyzed by a cascade of three enzymes; E1 (activation), E2 (conjugation) and E3 (ligation).  Members of the cullin family constitute the largest family of E3 ligases through binding with a small RING finger protein, ROC1 or ROC2, and with conserved protein motifs (F-box, SOCS box, BTB domain or WD40 repeat) present in as many as 300 - 400 proteins. Our current investigations combine biochemical and proteomic approaches to elucidate the regulation and to systematically identify the substrates of the cullin-RING E3 ubiquitin ligases (Mol. Cell 3:535; Mol. Cell 10:1511; Nat. Cell Biol. 5:1001, Nat Cell Biol 6:1003; Genes Dev. 20:2949-2954).