Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.22 (cdc2)
 8,319 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Growth factor-induced signals govern the expression of three D-type cyclins, which, in turn, function as regulatory subunits of cyclin-dependent kinases (cdks) to control cell cycle transitions during the late G1 interval. 32D myeloid cells, which self-renew as uncommitted precursors in interleukin 3 (IL-3), express cyclins D2 and D3 (but not D1) in complexes with cdk4 and cdk2. When transferred to granulocyte colony-stimulating factor (G-CSF), 32D cells stop dividing and terminally differentiate to mature neutrophils. Cyclin D and cdk4 expression ceased as cells underwent growth arrest in G-CSF, but cdk2 levels were sustained. 32D cells engineered to ectopically express D-type cyclins exhibited contracted G1 intervals with a compensatory lengthening of S phase but remained IL-3 dependent for cell growth; those overexpressing cyclins D2 and D3 (but not D1) were unable to differentiate and died in G-CSF. Cyclin D2 mutants, which cannot efficiently bind to, or functionally interact with, the retinoblastoma protein (pRb) or its relatives (p107) did not block differentiation. Conversely, the introduction of a catalytically inactive cdk4 mutant into cells overexpressing cyclin D2 restored their G-CSF response. The persistence of cdk2 and its predilection to functionally interact with cyclins D2 and D3 rather than D1 might explain the specificity of the differentiation blockade.
 ...
PMID:Inhibition of granulocyte differentiation by G1 cyclins D2 and D3 but not D1. 750 40

Deregulated expression of G1 cyclins D1 and D2 is a feature of some neoplasias. This study examined the altered expression of D1 and D2 cyclins, both the total pool and as associated with cdk4 and cdk2, at different stages of mouse mammary tumorigenesis. Three different mammary hyperplastic outgrowth lines, TM2, TM10 and TM12, and their respective tumors were examined. Increasing levels of the cyclin D1 protein pool, D1 binding to cdk4 and cdk2 and cdk4 kinase activity were closely correlated with tumorigenesis. In constrast, cyclin D2 binding to cdk4 was predominant in hyperplasias and much less in tumors, where cyclin D1 became predominant. However, the cyclin D2 pool showed increases of 15-65 times in hyperplasias compared with normal gland and further increases of 11-15 times in two of three different tumors. The message level for cyclin D1 increased only 2-3 times in tumors compared with normal gland. Cyclin D2 mRNA was highest in normal tissue and decreased only marginally in tumors. These results suggest that cyclin D2 functions uniquely from cyclin D1 in the early stages of mouse mammary tumor development. Cyclin D2 bound to cdk4 may act to guarantee a low level of kinase activity in hyperplasias and may be an attempt to direct the mammary epithelial cells through differentiation rather than proliferation. This interaction may be one of the negative regulatory mechanisms in the early stages in mouse mammary tumor development, until cyclin D1 totally replaces cyclin D2 binding to cdk4, which would activate the high levels of cdk4 kinase activity observed in neoplasias.
 ...
PMID:Mouse mammary hyperplasias and neoplasias exhibit different patterns of cyclins D1 and D2 binding to cdk4. 758 59

The spatial and temporal distribution of transcripts for the tumor suppressor gene Rb, transcription factor E2F1, cdc2 kinase, cyclins D1, D2, B1 and B2 during neurogenesis of the spinal cord was determined by in situ hybridization. The Rb and E2F1 transcripts were detectable in proliferating and differentiating cells. By contrast, cdc2, cyclins D1, B1 and B2 are expressed in the ventricular zone where proliferating cells are localized. Cyclin D2 mRNA was detectable only in the marginal zone of the developing neural tube. Electrophoretic mobility shift analyses demonstrated a changing pattern of DNA/protein complexes that bind to E2F binding site. These observations suggest that Rb and E2F1 may be involved in the early stages of neuronal differentiation in addition to the cell cycle regulation.
 ...
PMID:Expression of Rb, E2F1, cdc2, and D, and B cyclins in developing spinal cord. 762 53

We examined the expression and activity of Cdk4 and Cdk2 in resting, competent, and proliferating normal human T cells. Expression of Cdk4 but not of Cdk2 was induced in competent T cells independent of an IL-2 signal. This up-regulation of Cdk4 mRNA and protein was resistant to the immunosuppressant drugs cyclosporin A (CsA) and FK506. A further increase in Cdk4 expression was seen upon stimulation of competent T cells by IL-2, as was de novo expression of Cdk2. Cyclin D2, a Cdk4 partner, showed similar patterns of regulation as Cdk4. The increases in Cdk4 and cyclin D2 expression seen in competent T cells were functionally significant since Cdk4 immunoprecipitates from these cells phosphorylated recombinant RB protein in vitro. Despite the lack of an increase in the expression of Cdk2, a small pool of pre-existing Cdk2 protein detected in resting T cells could be activated upon induction of competence. These data demonstrate that 1) the signals that lead to induction of competence in T cells stimulate an IL-2-independent and CsA-resistant phase of Cdk4 and cyclin D2 expression, Cdk4 kinase activity, and Cdk2 kinase activity, and 2) IL-2 stimulates a second phase of Cdk4 and cyclin D2 expression and de novo expression of Cdk2 in these cells. The data show that the expression and activity of these major cell cycle regulatory proteins are controlled differentially by growth factors and indicate a role for Cdk4 and cyclin D2 in T-cell cycle entry and/or early G1 progression and for Cdk2 in later G1 progression and G1/S transition.
 ...
PMID:Differential requirements for interleukin-2 distinguish the expression and activity of the cyclin-dependent kinases Cdk4 and Cdk2 in human T cells. 780 27

Differentiation induction by 12-o-tetradecanoyl 13-acetate (TPA) results in the growth arrest of HL60 cells in the G1 phase. However, little is known about the changes of cell cycle-regulating genes during this differentiation process. We investigated the changes of mRNA for various cyclins (A, C, D1, D2, D3 and E) and cdk2. Synchronized HL60 cells began to proliferate immediately after release from cell cycle block and cell cycle synchrony was obvious until the second S phase. TPA-treated cells accumulated in G1 phase within 24 h and most of the cells were arrested in this phase at 36 h. The expression of cyclins and cdk2 was studied by Northern blot hybridization of the reverse-transcription polymerase chain reaction (RT-PCR). TPA treatment altered the expression of all genes studied. The expression of cdk2 and cyclin A mRNA was markedly down-regulated. Cyclin E mRNA expression was also prominently down-regulated from 12 h to 36 h, at which time a second increase of its expression was observed in control cells. In contrast, the expression of cyclin D1 mRNA was induced by TPA, while its expression in control cells was undetectable by Northern blot hybridization throughout the cell cycle. Cyclin C expression was faint and fluctuated irrelevant of cell cycle, but its expression in both control and TPA-treated cells was higher than at baseline. Cyclin D2 expression remained stable in control cells and TPA treatment resulted in slight down-regulation at 12 h, but no difference was observed after 24 h.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Changes of G1 cyclins, cdk2, and cyclin A during the differentiation of HL60 cells induced by TPA. 807 6

Cell-cell contact and TGF-beta can arrest the cell cycle in G1. Mv1Lu mink epithelial cells arrested by either mechanism are incapable of assembling active complexes containing the G1 cyclin, cyclin E, and its catalytic subunit, Cdk2. These growth inhibitory signals block Cdk2 activation by raising the threshold level of cyclin E necessary to activate Cdk2. In arrested cells the threshold is set higher than physiological cyclin E levels and is determined by an inhibitor that binds to cyclin E-Cdk2 complexes. A 27-kD protein that binds to and prevents the activation of cyclin E-Cdk2 complexes can be purified from arrested cells but not from proliferating cells, using cyclin E-Cdk2 affinity chromatography. p27 is present in proliferating cells, but it is sequestered and unavailable to interact with cyclin E-Cdk2 complexes. Cyclin D2-Cdk4 complexes bind competitively to and down-regulate the activity of p27 and may thereby act in a pathway that reverses Cdk2 inhibition and enables G1 progression.
 ...
PMID:p27Kip1, a cyclin-Cdk inhibitor, links transforming growth factor-beta and contact inhibition to cell cycle arrest. 828 31

The retinoblastoma gene product (Rb) can interact efficiently with two of three D-type G1 cyclins (D2 and D3) in vitro. Binding depended upon the minimal regions of Rb necessary for its growth-suppressive activity, as well as upon the D-type cyclin sequence motif shared with Rb-binding DNA tumor virus oncoproteins. Coexpression of the three D-type cyclins with the cyclin-dependent kinase (cdk4) in insect cells generated Rb kinase activity. By contrast, cyclins D2 and D3, but not D1, activated another such kinase, cdk2. Introduction of cyclin D2 and Rb into the Rb-deficient cell line SAOS-2 led to overt Rb hyperphosphorylation, whereas Rb, expressed alone or together with cyclin D1, remained unphosphorylated. Cyclin D2-dependent phosphorylation inhibited its binding to the transcription factor E2F and reversed the Rb G1 exit block in the cell cycle. Thus, all D-type cyclins do not function equivalently, and one of them plays a major role in reversing the cycle-blocking function of a known tumor suppressor.
 ...
PMID:Functional interactions of the retinoblastoma protein with mammalian D-type cyclins. 834 2

To investigate the possibility of differing roles for cyclins D1 and D2 in breast epithelial cells, we examined the expression, cell cycle regulation and activity of these two G1 cyclins in both 184 normal breast epithelial cells and T-47D breast cancer cells. Synchronisation studies in 184 cells demonstrated that cyclin D1 and cyclin D2 were differentially regulated during G1, with cyclin D2 abundance increasing by 3.7-fold but only small changes in cyclin D1 abundance observed. The functional consequences of increased cyclin D2 expression were examined in T-47D cells, which express no detectable cyclin D2. Induced expression of cyclin D2 resulted in increases in cyclin E expression, pRB phosphorylation and the percentage of cells in S-phase, while constitutive expression resulted in a consistent trend toward reduced dependence on serum for continued proliferation. Thus, cyclin D2 is a positive regulator of G1 progression in breast cells analogous to the well-documented effects of cyclin D1. Indeed, equimolar concentrations of inducible cyclin D1 and D2 resulted in quantitatively similar cell cycle effects. Marked divergence was found, however, in the CDKs activated by the two cyclins in breast epithelial cells. Cyclin D2 complexes contained a higher Cdk2/Cdk4 ratio than cyclin D1 complexes. The cyclin D2-associated kinase activity was largely inhibited by Cdk2-specific inhibitors and could phosphorylate histone H1, a substrate for Cdk2 but not for Cdk4 and Cdk6. Therefore, cyclin D2 preferentially activated Cdk2 in breast epithelial cells. In contrast, Cdk4 and Cdk6 were predominantly responsible for cyclin D1-associated kinase activity as previously reported. Thus, although cyclins D1 and D2 elicited similar effects on breast epithelial cell cycle progression they appeared to achieve this end via activation of different CDKs. This is the first evidence of cyclin D2 activating Cdk2 in mammalian cells thus providing further evidence that D-type cyclins are not necessarily redundant.
 ...
PMID:Cyclin D2 activates Cdk2 in preference to Cdk4 in human breast epithelial cells. 917 93

Transfection and transgenic mouse experiments supported an oncogenic role for cyclin D1 in breast cancer. We recently reported that noninvasive carcinoma in situ lesions of the human breast overexpress cyclin D, suggesting that this molecular event may represent a valuable target for chemoprevention. The purpose of the present series of investigations was to identify agents which could reduce the cyclin D expression of breast cells. We report that 9-cis retinoic acid (9-cis RA) and all trans retinoic acid (tRA) inhibited the cyclin D1 and D3 expression levels of human MCF-7, ZR-75 and T-47D breast carcinoma cells in vitro. Where detectable, similar trends were observed in the immortalized, HBL-100 and MCF-10A breast cell lines. Cyclin D2 was undetectable. The effect of retinoids was both dose- and time-dependent, and correlated with altered cell cycle kinetics and proliferative status. Retinoids were also found to inhibit the expression levels of other cell cycle related proteins, including Cdk2 and Cdk4, resulting in lower kinase activities. In contrast to other breast prevention studies, no synergistic effect was observed with retinoids and tamoxifen. The data indicate that retinoids can potently reduce cyclin D expression levels in a variety of breast cell lines in vitro, and suggest further consideration of this mechanism for the chemoprevention of breast cancer.
 ...
PMID:Inhibition of cyclin D expression in human breast carcinoma cells by retinoids in vitro. 923 83

The inability of myocytes to reenter the cell cycle in vitro may result from a block in the activation of cyclins and cyclin-dependent kinases (cdk). This inhibition may not occur in vivo because myocyte proliferation is present in the failing heart. Thus, cardiac failure was induced by ventricular pacing in dogs, and changes in the quantity of cyclin D2, cyclin A, cyclin B, cdk2, and cell-division cycle-2 (cdc2) in control and paced myocytes were measured. The kinase activity of these nuclear proteins was also established. Finally, DNA synthesis and mitotic indices in myocytes were evaluated. Cyclin D2 in myocytes increased 7-fold after pacing, and cyclin D2-associated kinase activity increased 3-fold. Similarly, cyclin A quantity and activity increased 4-fold. Comparable changes were observed for cyclin B. cdc2 protein increased 8-fold, and cdk2 and cdc2 activity increased 3-fold and 5-fold, respectively. DNA synthesis was detected in 556 myocyte nuclei/10(6) and 2,467 myocyte nuclei/10(6) in control and paced hearts, respectively. Corresponding mitotic indices were 16/10(6) and 95/106, respectively. In conclusion, myocytes react to cardiac failure by activating cyclins and cdk, which are coupled with cell regeneration and the recovery of muscle mass.
 ...
PMID:Activation of cyclins and cyclin-dependent kinases, DNA synthesis, and myocyte mitotic division in pacing-induced heart failure in dogs. 1061 5


1 2 Next >>