Human cell division is regulated primarily at the G1-to-S or the G2-to-M boundaries. The sequential activation of cyclin-dependent kinases (CDKs) and their subsequent phosphorylation of critical substrates promote orderly progression through the cell cycle. The complexes formed by CDK4 and the D-type cyclins (e.g., D1, D2, D3, ) are involved in the control of cell proliferation during the G1 phase. CDK4 is inhibited by p16,
also known as cyclin-dependent kinase inhibitor-2 (CDKN2A;).
Demetrick et al. (1994) mapped the CDK4 gene to 12q13 by fluorescence in situ hybridization. CDK2 maps to the same band. By fluorescence in situ hybridization, Mitchell et al. (1995) mapped CDK4 to 12q14 and oncluded that it is distal to GLI and CHOP, which they placed at 12q13.3-q14.1; and proximal to MDM2), which they placed at 12q14.3-q15.
NCBI Summary:
The protein encoded by this gene is a member of the Ser/Thr protein kinase family. This protein is highly similar to the gene products of S. cerevisiae cdc28 and S. pombe cdc2. It is a catalytic subunit of the protein kinase complex that is important for cell cycle G1 phase progression. The activity of this kinase is restricted to the G1-S phase, which is controlled by the regulatory subunits D-type cyclins and CDK inhibitor p16(INK4a). This kinase was shown to be responsible for the phosphorylation of retinoblastoma gene product (Rb). Mutations in this gene as well as in its related proteins including D-type cyclins, p16(INK4a) and Rb were all found to be associated with tumorigenesis of a variety of cancers. Multiple polyadenylation sites of this gene have been reported. [provided by RefSeq, Jul 2008]
General function
Cell death/survival, Cell cycle regulation
Comment
Harbour et al. (1999) presented evidence that phosphorylation of the C-terminal region of RB (retinoblastoma protein) by CDK4/CDK6 initiates successive intramolecular interactions between the C-terminal region and the central pocket. The initial interaction displaces histone deacetylase from the pocket, blocking active transcriptional repression by RB. This facilitates a second interaction that leads to phosphorylation of the pocket by CDK2 and disruption of pocket structure. These intramolecular interactions provide a molecular basis for sequential phosphorylation of RB by CDK4/CDK6 and CDK2. CDK4/CDK6 is activated early in G1, blocking active repression by RB. However, it is not until near the end of G1, when cyclin E is expressed and CDK2 is activated, that RB is prevented from binding and inactivating E2F.
Cellular localization
Cytoplasmic, Nuclear
Comment
Ovarian function
Luteinization
Comment
Tsutsui et al. (1999) showed that CDK4(-/-) mice had perturbed corpus luteum formation in the ovary.Inhibition of CDK4/6 kinases causes production of aneuploid oocytes by inactivating the spindle assembly checkpoint and accelerating first meiotic progression. Dong F et al. (2021) Cyclin D-CDK4/6 complex mediates the transition from the G1 to S phase in mammalian somatic cells. Meiotic oocytes pass through the G2/M transition and complete the first meiosis to reach maturation at the metaphase of meiosis II without intervening S phase, while Cyclin D-CDK4/6 complex is found to express during meiotic progression. Whether Cyclin D-CDK4/6 complex regulates meiotic cell cycle progression is not known. Here, we found its different role in oocyte meiosis: Cyclin D-CDK4/6 complex served as a regulator of spindle assembly checkpoint (SAC) to prevent aneuploidy in meiosis I. Inhibition of CDK4/6 kinases disrupted spindle assembly, chromosome alignment and kinetochore-microtubule attachments, but unexpectedly accelerated meiotic progression by inactivating SAC, consequently resulting in production of aneuploid oocytes. Further studies showed that the MPF activity decrease before first polar body extrusion was accelerated probably by inactivation of the SAC to promote ubiquitin-mediated cyclin B1 degradation. Taken together, these data reveal a novel role of Cyclin D-CDK4/6 complex in mediating control of the SAC in female meiosis I.//////////////////
Expression regulated by
FSH, LH, Steroids, cyclins
Comment
Xiong et al. (1992) showed that cyclin D2 acts as a positive regulator of cell cycle progression by its ability to bind cyclin-dependent kinases (cdks) 4 or 6 and thereby activate a cascade of events that permits progression through G1phase of the cell cycle. Furthermore, Robker et al. (1998) showed that that FSH and estradiol regulate granulosa cell
proliferation during the development of preovulatory follicles by increasing levels of cyclin D2 relative to p27Kip1 and that LH terminates follicular growth by down-regulating cyclin D2 concurrent with up-regulation of p27Kip1 and p21Cip1.Granulosa cell expression of G1/S phase cyclins and cyclin-dependent kinases in PMSG-induced follicle growth. Cannon JD et al. Follicular development involves a complex orchestration of granulosa cell proliferation and differentiation. It is becoming increasingly apparent that the rate of granulosa cell proliferation declines as follicles reach the large antral status, prior to an ovulatory gonadotropin stimulus, although a precise time course and mechanism for this decline has not been described. The goal of the present study was to characterize granulosa cell proliferation following the onset of antral follicle growth in PMSG-primed immature rats, with emphasis on G1/S phase cyclins and cyclin-dependent kinases. Flow cytometric analysis demonstrated that the percentage of granulosa cells in S phase peaked 24-30h post-PMSG and declined to control levels 48h after PMSG administration. Expression of both Cyclin D2 and Cdk 4 was highest 12h post-PMSG and decreased to control levels by 48h. In addition, Cdk 2 protein increased transiently 12-24h after PMSG. Cyclin E expression increased significantly by 12h but remained elevated through 48h, and multiple isoforms of Cyclin E were observed with increased proliferation. Both Cdk 4 and Cdk 2 activity parallel protein expression, although, changes in Cdk 2 were more marked. Levels of mRNA for the cell cycle inhibitors p21(CIP1) and p27(KIP1) increased significantly by 48h post-PMSG. These results demonstrate that PMSG-stimulated movement of granulosa cells across the G1/S boundary during follicle growth is transient. In addition, the control of granulosa cell proliferation may reside through the regulation of both Cdk 2 and Cdk 4.
Ovarian localization
Oocyte, Granulosa, Luteal cells
Comment
Expression and cellular distribution of cyclin-dependent kinase 4 (Cdk4) and connexin 43 (Cx43) in porcine oocytes before and after in vitro maturation. Kempisty B 2013 et al.
It is recognised that connexin 43 (Cx43) and cyclin-dependent kinase 4 (Cdk4) are involved in the cumulus cell-oocyte communication via gap junctions and the control of cell cycle progress. However, little is known about their mRNA expression pattern and encoded proteins distribution in porcine oocytes during in vitro maturation (IVM). Cumulus-oocyte complexes (COCs) were collected from 31 puberal crossbred Landrace gilts and analysed for their Cdk4 and Cx43 mRNA expression using RQ-PCR and for the respective protein expression by confocal microscopic observations. An increased Cdk4 and Cx43 mRNA expression was found in oocytes after IVM (P < 0.001 and P < 0.05, respectively). Confocal microscopic observations revealed a significant increase of Cdk4 protein expression in the cytoplasm of oocytes during the maturation process. The localisation of Cx43 changed from zona pellucida before to cytoplasm of oocytes after IVM. It is supposed that the increased expression of Cdk4 and Cx43 mRNA in oocytes after IVM is linked with the accumulation of a large amount of templates during the process of oocyte maturation. The translocation especially of Cx43 from the zona pellucida into the cytoplasm may be associated with a decrease in gap junction activity in fully grown porcine oocytes. Both Cdk4 and Cx43 can be used as 'checkpoints 'of oocyte maturation.
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Rhee et al. (1995) found that the Cdk family genes are expressed not only in dividing but also in terminally differentiated mouse germ cells, suggesting their possible function during both cell division and differentiation. Specifically, Cdk4, Cdc2, and Cdk2 are expressed in granulosa cells of ovarian follicles.
Follicle stages
Antral, Preovulatory, Corpus luteum
Comment
Hampl A, et al reported levels and interactions of p27, cyclin D3, and CDK4 during the formation and maintenance of the corpus luteum in mice.
Phenotypes
Mutations
2 mutations
Species: mouse
Mutation name: None
type: null mutation fertility: infertile - ovarian defect Comment:David S. Moons, et al 2002 reported Intact Follicular Maturation and Defective Luteal
Function in Mice Deficient for Cyclin- Dependent Kinase-4.
Cell cycle progression of granulosa cells is critical for ovarian function, especially follicular maturation. During follicular
maturation, FSH induces cyclin D2, which promotes G1 progression by activating cyclin-dependent kinase-4 (Cdk4).
Because cyclin D2-deficient mice exhibit a block in follicular growth, cyclin D2/Cdk4 has been hypothesized to be required
for FSH-dependent proliferation of granulosa cells. Here the authors investigate ovarian function in Cdk4-knockout mice . Cdk4-/- females were sterile, but the morphology of their ovaries appeared normal before sexual
maturation. The number of preovulatory follicles and the ovulation efficiency were modestly reduced in
gonadotropin-treated Cdk4-/- mice. However, unlike cyclin D2-deficient mice, Cdk4-/- mice showed no obvious defect in
FSH-induced proliferation of granulosa cells. Cdk4-/- ovaries displayed normal preovulatory expression of aromatase, PR,
and cyclooxygenase-2. Postovulatory progesterone secretion was markedly impaired in Cdk4-/- mice, although granulosa
cells initiated luteinization with induction of p450 side-chain cleavage cytochrome and p27Kip1. Progesterone treatment
rescued implantation and restored fertility in Cdk4-/- mice. Serum PRL levels after mating were significantly reduced in
Cdk4-/- mice, suggesting the involvement of perturbed PRL regulation in luteal failure. Thus, Cdk4 is critical for luteal
function, and some redundant protein(s) can compensate for the absence of Cdk4 in proliferation of granulosa cells.
Species: mouse
Mutation name: CDK4(-/-)
type: null mutation fertility: infertile - ovarian defect Comment:Tsutsui et al. (1999) showed, that CDK4(-/-) mice survived embryogenesis and showed growth retardation and reproductive dysfunction associated with perturbed corpus luteum formation in the ovary.