Harper et al. (1993) used an improved 2-hybrid system to isolate human genes encoding CDK-interacting proteins (CIPs) which they called CIP. CIP1 was found to encode a novel 21-kd protein that is found in immunoprecipitates of cyclin A, cyclin D1, cyclin E, and CDK2. The cyclin-dependent kinase CDK2 associates with cyclins A, D, and E and has been implicated in the control of the G1 to S phase transition in mammals. CIP1is a potent, tight-binding inhibitor of CDKs and can inhibit the phosphorylation of the retinoblastoma protein by several of these complexes. The preferred name and symbol for this gene are cyclin-dependent kinase inhibitor 1A (CDKN1A). Also referred to as WAF1, p21 or CDKN1, this protein inhibits cyclin-kinase activity, is tightly regulated at the transcriptional level by p53, and probably serves as the effector of p53 cell cycle control. The WAF1-encoded protein p21 mediates p53 suppression of tumor cell growth. Overexpression of p21 in a tumor cell line suppresses colony formation similar to that resulting from p53 overexpression. Expression profiling of purified mouse gonadal somatic cells during the critical time window of sex determination reveals novel candidate genes for human sexual dysgenesis syndromes Beverdam A, et al.
NCBI Summary:
This gene encodes a potent cyclin-dependent kinase inhibitor. The encoded protein binds to and inhibits the activity of cyclin-cyclin-dependent kinase2 or -cyclin-dependent kinase4 complexes, and thus functions as a regulator of cell cycle progression at G1. The expression of this gene is tightly controlled by the tumor suppressor protein p53, through which this protein mediates the p53-dependent cell cycle G1 phase arrest in response to a variety of stress stimuli. This protein can interact with proliferating cell nuclear antigen, a DNA polymerase accessory factor, and plays a regulatory role in S phase DNA replication and DNA damage repair. This protein was reported to be specifically cleaved by CASP3-like caspases, which thus leads to a dramatic activation of cyclin-dependent kinase2, and may be instrumental in the execution of apoptosis following caspase activation. Mice that lack this gene have the ability to regenerate damaged or missing tissue. Multiple alternatively spliced variants have been found for this gene. [provided by RefSeq, Sep 2015]
Cellular hallmarks of aging emerge in the ovary prior to primordial follicle depletion. Ansere VA et al. (2021) Decline in ovarian reserve with advancing age is associated with reduced fertility and the emergence of metabolic disturbances, osteoporosis, and neurodegeneration. Recent studies have provided insight into connections between ovarian insufficiency and systemic aging, although the basic mechanisms that promote ovarian reserve depletion remain unknown. Here, we sought to determine if chronological age is linked to changes in ovarian cellular senescence, transcriptomic, and epigenetic mechanisms in a mouse model. Histological assessments and transcriptional analyses revealed the accumulation of lipofuscin aggresomes and senescence-related transcripts (Cdkn1a, Cdkn2a, Pai-1 and Hmgb1) significantly increased with advancing age. Transcriptomic profiling and pathway analyses following RNA sequencing, revealed an upregulation of genes related to pro-inflammatory stress and cell-cycle inhibition, whereas genes involved in cell-cycle progression were downregulated; which could be indicative of senescent cell accumulation. The emergence of these senescence-related markers preceded the dramatic decline in primordial follicle reserve observed. Whole Genome Oxidative Bisulfite Sequencing (WGoxBS) found no genome-wide or genomic context-specific DNA methylation and hydroxymethylation changes with advancing age. These findings suggest that cellular senescence may contribute to ovarian aging, and thus, declines in ovarian follicular reserve. Cell-type-specific analyses across the reproductive lifespan are needed to fully elucidate the mechanisms that promote ovarian insufficiency.//////////////////
Jirawatnotai S, et al 2003 reported that the CDK inhibitors p27Kip1 and p21Cip1cooperate to restrict proliferative life span in differentiating ovarian cells.
The timing of cellular exit from the cell cycle during differentiation is specific for each cell type or lineage. Granulosa cells in the ovary establish quiescence within several hours following the ovulation-inducing LH surge, while they undergo differentiation into corpora lutea. The expression of Cdk inhibitors p21(Cip1) and p27(Kip1) is upregulated during this process, suggesting that these cell cycle inhibitors are involved in restricting proliferative capacity of differentiating granulosa cells. The authors demonstrate that the lack of p27(Kip1) and p21(Cip1) synergistically render granulosa cells extended proliferative life span. Immunohistochemical analyses demonstrated that corpora lutea of p27(Kip1), p21(Cip1) double-null mice showed large numbers of cells with bromodeoxyuridine (BrdU) incorporation and high proliferative cell nuclear antigen (PCNA) expression, which were more remarkable than those in p27(Kip1) single-deficient mice showing modest hyperproliferation. In contrast, differentiating granulosa cells in p21(Cip1)-deficient mice ceased proliferation similarly to those in wild-type mice. Interestingly, granulosa cells isolated from p27(Kip1), p21(Cip1) double-null mice exhibited markedly prolonged proliferative life span in culture, unlike cells with other genotypes. Cultured p27(Kip1), p21(Cip1) double-null granulosa cells maintained expression of steroidogenic enzymes and gonadotropin receptors through 8-10 passages, and could undergo further differentiation in responses to cAMP accumulation. Thus, the cooperation of p27(Kip1) and p21(Cip1) is critical for withdrawal of granulosa cells from the cell cycle, in concert with luteal differentiation and possibly culture-induced senescence.
Gene whose expression is detected by cDNA array hybridization: oncogenes, tumor
suppressors, cell cycle regulators Rozenn Dalbis-Tran and Pascal Mermilloda
Expression regulated by
LH
Comment
LH induced the expression of the cell cycle inhibitor p27Kip1 between 12 and 24 h (p21Cip1was induced within 4 h) and remained elevated specifically in luteal tissue (Robker et al., 1998).
Ovarian localization
Granulosa
Comment
LH terminates follicular growth by down-regulating cyclin D2 concurrent with up-regulation of p27Kip1 and p21Cip1 (Robker et al., 1998).