The CDK2 protein was highly
homologous to p34(CDC2) kinase and more significantly homologous to Xenopus Eg1 kinase, suggesting that CDK2 is
the human homolog of Eg1. The human CDC2 and CDK2 genes were both able to complement the inviability of a null
allele of S. cerevisiae, CDC28. However, CDK2 was unable to complement cdc2 mutants in fission yeast
Schizosaccharomyces pombe under the condition where the human CDC2 gene could complement them. CDK2 mRNA
appeared late in G1 or in early S phase, slightly before CDC2 mRNA, after growth stimulation in the normal human
fibroblast cells. Thus, 2 different CDC2-like kinases appear to regulate the human cell cycle at different stages.
NCBI Summary:
This gene encodes a member of a family of serine/threonine protein kinases that participate in cell cycle regulation. The encoded protein is the catalytic subunit of the cyclin-dependent protein kinase complex, which regulates progression through the cell cycle. Activity of this protein is especially critical during the G1 to S phase transition. This protein associates with and regulated by other subunits of the complex including cyclin A or E, CDK inhibitor p21Cip1 (CDKN1A), and p27Kip1 (CDKN1B). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2014]
New insights into Cdk2 regulation during meiosis. Isoda M et al. (2016)//////////////////
Cdk2 Activity is Essential for the First to Second Meiosis Transition in Porcine OocytesSugiura K, et al .
The meiotic progression of Xenopus oocytes has been suggested to depend on the activity of cyclin-dependent kinase 2 (Cdk2). We examined whether Cdk2 is involved in the regulation of mammalian oocyte meiosis by injecting porcine oocytes with anti-Cdk2 antibody. At first, the cross-reactivity of the anti-Cdk2 antibody with Cdc2 kinase was evaluated by immunoprecipitation and immunoblotting experiments using porcine granulosa cell extract, and no cross-reactivity with Cdc2 kinase was observed in the antibody used. In the anti-Cdk2 antibody-injected group, 50.7% of the oocytes were arrested in the second metaphase after 50 h of culture and this rate was significantly lower than those in the non-injected intact oocytes or the oocytes injected with mouse IgG (84.5% and 86.7%, respectively). Most of the other oocytes in the antibody-injected group formed a pronucleus without polar bodies or with only one polar body. The cyclin B1 amount in the antibody-injected and activated oocytes was dramatically decreased compared with that in the intact or mouse IgG-injected oocytes after 50 h of culture. These results suggest that Cdk2 is involved in the meiotic maturation of mammalian oocytes, and that the block of Cdk2 activity results in the failure of cyclin B1 accumulation and second meiosis induction.
Gene whose expression is detected by cDNA array hybridization: oncogenes, tumor
suppressors, cell cycle regulators Rozenn Dalbi?Tran and Pascal Mermilloda
Expression regulated by
FSH
Comment
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
Comment
Rhee K, et al 1995 reported that 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.
The roles of the cyclin dependent kinase (Cdk) family in murine germ cell
development have been examined by studying the expression of five Cdk family
genes (Cdc2, Cdk2, Cdk4, Pctaire-1, and Pctaire-3) in mouse reproductive
organs. Northern blot and in situ hybridization analyses revealed distinctive
expression patterns of these genes with striking cellular, lineage, and
developmental stage specificity. Cdc2 and Cdk2 were expressed in premeiotic spermatocytes in
the testis, and Cdc2, Cdk2, and Cdk4 expressed in granulosa cells of ovarian
follicles. With regard to Pctaire-1 and Pctaire-3, the
highest levels of expression were observed in postmeiotic spermatids.
Immunoblot analysis also revealed the presence of high levels of Pctaire-1 in
postmeiotic germ cells. These results suggest that Cdk family kinases may exhibit
various functions in germinal and somatic cells during gametogenesis, not only in
the cell cycle but also in other regulatory processes, including differentiation.
Hirai T, et al reported the iIsolation and characterization of goldfish cdk2, a cognate variant
of the cell cycle regulator cdc2.
Goldfish cdk2 is a cognate variant of the cell cycle regulator cdc2. The predicted
protein sequence shows strong homology to the other known cdk2 (88% for
Xenopus and 90% for human). A monoclonal antibody against the C-terminal
sequence of goldfish cdk2 recognized a 34-kDa protein in extracts from various
goldfish tissues. The protein level was high in such tissues as testis and ovary
containing actively dividing cells. Protein cdk2 binds to p13sucl, the fission yeast
suc1+ gene product, but not to cyclin B, with which cdc2 forms a complex. The
kinase activity of cdk2 increased 30-fold when oocytes matured, although its
protein level did not remarkably change. Anti-cdk2 immunoprecipitates from
32P-labeled mature oocyte extracts contained a 47-kDa protein, which was not
recognized by either anti-cyclin A or anti-cyclin B antibody, indicating complex
formation of cdk2 with a protein other than cyclins A or B.
Follicle stages
Comment
Distinct roles for the mammalian A-type cyclins during oogenesis Persson JL, et al .
There are two A-type cyclins in higher vertebrates, cyclin A1 and A2. Targeted mutagenesis has shown that cyclin A2 is essential for early embryonic development while cyclin A1 is required only for male meiosis. The embryonic lethality of cyclin A2 knockout mice has obviated understanding its role in other aspects of mammalian development, including the germ line. We reported previously that cyclin A2 expression in the male germ line is consistent with a role in both mitotic and meiotic cell cycles. Using in situ hybridization and immunohistochemistry, we now observe high levels of cyclin A2 in granulosa cells and less-abundant but readily detectable expression in ovarian and ovulated oocytes. A decrease in cyclin A2 protein was observed in oocytes from embryonic stages to post-natal and adult ovaries. Interestingly, cyclin A2 protein was nuclear in oocytes from embryonic day 13.5 to 15.5, changing to largely cytoplasmic in oocytes from embryonic day 16.5 to post-natal and adults. Readily detectable expression of the cyclin-dependent kinases Cdk1 and Cdk2, two common partners for the A-type cyclins, was observed in granulosa cells and oocytes at all stages of folliculogenesis. Cdk1 was predominantly cytoplasmic, whereas Cdk2 was both cytoplasmic and nuclear in oocytes. No cyclin A1 expression, at either the mRNA level or the protein level was detected in either embryonic or adult ovaries, consistent with the full fertility observed in female cyclin A1-deficient mice. These results suggest that in the female germ line, cyclin A2 but not cyclin A1 has distinct roles in both mitosis and meiosis.
Phenotypes
Mutations
2 mutations
Species: mouse
Mutation name: None
type: null mutation fertility: infertile - ovarian defect Comment: Cyclin-dependent kinase 2 is essential for meiosis but not for mitotic cell division in mice
Ortega S, et al .
We targeted the locus encoding the cyclin-dependent kinase 2 (CDK2) by homologous recombination in mouse embryonic stem (ES) cells. Embryonic fibroblasts lacking CDK2 proliferate normally and become immortal after continuous passage in culture. Elimination of a conditional Cdk2 allele in immortal cells does not have a significant effect on proliferation. Cdk2-/- mice are viable and survive for up to two years, indicating that CDK2 is also dispensable for proliferation and survival of most cell types. But CDK2 is essential for completion of prophase I during meiotic cell division in male and female germ cells, an unforeseen role for this cell cycle kinase.
Species: human
Mutation name: type: naturally occurring fertility: infertile - ovarian defect Comment: The genetics of human infertility by functional interrogation of SNPs in mice. Singh P et al. (2015) Infertility is a prevalent health issue, affecting ∼15% of couples of childbearing age. Nearly one-half of idiopathic infertility cases are thought to have a genetic basis, but the underlying causes are largely unknown. Traditional methods for studying inheritance, such as genome-wide association studies and linkage analyses, have been confounded by the genetic and phenotypic complexity of reproductive processes. Here we describe an association- and linkage-free approach to identify segregating infertility alleles, in which CRISPR/Cas9 genome editing is used to model putatively deleterious nonsynonymous SNPs (nsSNPs) in the mouse orthologs of fertility genes. Mice bearing "humanized" alleles of four essential meiosis genes, each predicted to be deleterious by most of the commonly used algorithms for analyzing functional SNP consequences, were examined for fertility and reproductive defects. Only a Cdk2 allele mimicking SNP rs3087335, which alters an inhibitory WEE1 protein kinase phosphorylation site, caused infertility and revealed a novel function in regulating spermatogonial stem cell maintenance. Our data indicate that segregating infertility alleles exist in human populations. Furthermore, whereas computational prediction of SNP effects is useful for identifying candidate causal mutations for diverse diseases, this study underscores the need for in vivo functional evaluation of physiological consequences. This approach can revolutionize personalized reproductive genetics by establishing a permanent reference of benign vs. infertile alleles.//////////////////