Cell cycle progression is controlled by the cyclindependent kinases (CDKs). CDKs are the catalytic partners of the cyclins [reviewed in 1]. Regulators of G1 progression in mammalian cells include D-type cyclins (D1, D2, D3), and cyclin E [2]. D-type cyclins are associated with either Cdk4 or Cdk6, while cyclin E is associated with Cdk2 [3]. Cyclin kinase inhibitors (CKIs) bind to CDKs and inhibit their activity. p21 is a CKI that inhibits G1 cyclin/CDK complexes [4, 5]. p21 effectively inhibits Cdk2, Cdk3, Cdk4, and Cdk6 which have a direct role in the G1/S transition, but it is a poor inhibitor of other known Cdks [6]. The p21 cDNA was cloned independently by several groups using a number of different screening strategies. Using a yeast two-hybrid screen, p21 was identified as a CDK binding protein, and was subsequently named CIP1, for CDK-interacting protein 1 [4]. Microsequencing of a protein that interacted with CDKs led to its cloning using PCR [5]. It was also identified as the product of a gene activated by wild-type p53, and it was named WAF1 (wild-type p53-activated factor)[7]. Later p21 was cloned using an expression screen designed to identify inhibitors of DNA synthesis from senescent fibroblasts, and it was named SDI1 (senescent cell-derived inhibitor [8]. Using subtractive hybridization, the p21 cDNA was isolated based on its increased expression in human melanoma cells that were induced to differentiate, and it was named MDA-6, for melanoma differentiation-associated protein [9]. Seven CKIs have been identified so far, which can be divided into two families. The first family contains p21, p27 [10, 11], and p57 [12, 13]. These CKIs share similarities at their amino terminus and have a broad specificity for CDKs. p16 [14, 15], p15 [16], p18, and p19 [17, 18] form a second family with a more restricted CDK specificity. The ARF-INK4a locus, which encodes both p16 and the unrelated protein p19, is a major target for inactivation in human cancers [for review see 19a]. p21 does not appear to play a significant role in tumorigenesis, and mutations in the p21 gene appear rare in human tumors. Mice deficient in p21 did not develop any tumors, or have any alterations in their organs [20, 21]. p21 has been shown to inhibit proliferation both in vitro and in vivo, and introduction of p21 expression constructs into normal [4] and tumor cell lines [7] results in cell cycle arrest in G1 [6]. Recently it has been shown that in addition to inducing G1 arrest, p21 may also mediate G2 arrest [22, 23]. While p21 usually acts as a negative regulator of the cell-cycle, induction of p21 expression by mitogenic stimuli has been observed by several investigators [24–27]. Thus far, the significance of p21 induction following mitogenic activation of the cell cycle is not well understood. Proliferation of myeloid progenitor cells is compromised in mice lacking p21, suggesting a positive role for p21 in the proliferation of these cells [26]. Exit from the cell cycle is a prerequisite for terminal differentiation, and p21 expression is induced during terminal differentiation both in vitro [24, 28–30] and in vivo [31–33, reviewed in 34]. Ectopic expression of p21 has been shown to promote differentiation of the megakaryoblastic leukemia cell line CMK [35] and the myelomonocytic cell line U937 [36]. Interestingly, p21 was also shown to inhibit differentiation in terminally differentiated keratinocytes [37]. Disruption of p21 in normal diploid fibroblasts resulted in an extension of in vitro life span and a bypass of senescence [38]. Cells lacking p21 appear to undergo apoptosis normally (20, 38), although in some systems p21 has been found to protect cells from apoptosis [39, 40] or to promote apoptosis [41, 42 …