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)

Corneal endothelial cells have a limited capacity for proliferation. Upon transformation with the SV40 large T antigen, however, these cells undergo division and grow rapidly. In order to gain insight into the control mechanisms that determine this proliferative switch, we investigated the expression level and activity of various known cell cycle-regulatory proteins in these cells. Primary human and rabbit corneal endothelial cells were transduced in vitro with a replication-defective adenovirus containing SV40 large T antigen, and subsequently the expression and activity of cell cycle-regulatory proteins was analyzed. Cells transduced with large T antigen exhibited strongly increased activity of cyclin-dependent kinases. This increase correlated with the elevated expression of various cyclin-dependent kinase subunits, such as cyclin A, and to a lesser extent, cyclin D, cdk2, and cdk4. Furthermore, the expression of two cyclin-dependent kinase inhibitors, p21(WAF1) and p27(KIP1), which was high in primary human cells (but not in primary rabbit cells), was strongly reduced in large T-antigen transduced cells. Thus, the remarkably low proliferative activity of normal human corneal endothelial cells appears to be regulated at two levels: the expression of certain cell cycle-regulatory proteins that are essential for cell cycle progression is extremely low (cyclin A) or somewhat low (cdk2 and cdk4); but the amount of p21 and p27, inhibitors of cell cycle progression, is very high. As a consequence, the enzymatic activity of cyclin-dependent kinase is below detectable levels. However, the growth-inhibitory status of these components is clearly reversible: upon transduction with large T antigen, the expression of cyclin A, cyclin D, cdk2, and cdk4 is induced, whereas the expression of p21 and p27 is inhibited, and the cells proliferate. Thus, our study provides insight into the molecular basis of the attenuated proliferation of corneal endothelial cells and suggests potential targets that could be manipulated for the purpose of therapeutic interventions aimed at renewed cell growth.
 ...
PMID:Expression and activity of cell cycle-regulatory proteins in normal and transformed corneal endothelial cells. 1032 66

c-myc is a cellular proto-oncogene associated with a variety of human cancers and is strongly implicated in the control of cellular proliferation, programmed cell death, and differentiation. We have previously reported the first isolation of a c-myc-null cell line. Loss of c-Myc causes a profound growth defect manifested by the lengthening of both the G1 and G2 phases of the cell cycle. To gain a clearer understanding of the role of c-Myc in cellular proliferation, we have performed a comprehensive analysis of the components that regulate cell cycle progression. The largest defect observed in c-myc-/- cells is a 12-fold reduction in the activity of cyclin D1-Cdk4 and -Cdk6 complexes during the G0-to-S transition. Downstream events, such as activation of cyclin E-Cdk2 and cyclin A-Cdk2 complexes, are delayed and reduced in magnitude. However, it is clear that c-Myc affects the cell cycle at multiple independent points, because restoration of the Cdk4 and -6 defect does not significantly increase growth rate. In exponentially cycling cells the absence of c-Myc reduces coordinately the activities of all cyclin-cyclin-dependent kinase complexes. An analysis of cyclin-dependent kinase complex regulators revealed increased expression of p27(KIP1) and decreased expression of Cdk7 in c-myc-/- cells. We propose that c-Myc functions as a crucial link in the coordinate adjustment of growth rate to environmental conditions.
 ...
PMID:c-Myc regulates cyclin D-Cdk4 and -Cdk6 activity but affects cell cycle progression at multiple independent points. 1037 16

The heart is a postmitotic organ unable to regenerate after injury. The mechanisms controlling cell cycle arrest in cardiomyocytes are still unknown. Adenoviral delivery of E2F-1 to primary rat cardiomyocytes resulted in an increase in the expression of key cell cycle activators and apoptosis in >90% of the cells. However, insulin-like growth factor I (IGF-I) rescued cardiomyocytes from E2F-1-induced apoptosis. Furthermore, overexpression of E2F-1 in the presence of IGF-I induced the specific downregulation of total p21(CIP1) and p27(KIP1) protein levels and their dissociation from cyclin-dependent kinases (cdks). In contrast, p16(INK4) and p57(KIP2) protein levels and their association with cdks remained unaltered. The dissociation of p21(CIP1) and p27(KIP1) from their cdk complexes correlated well with the activation of cdk2, cdk4, and cdk6 and the release from cell cycle arrest. Under these circumstances, the number of cardiomyocytes in S phase rose from 1.2% to 23%. These results indicate that IGF-I renders cardiomyocytes permissive for cell cycle reentry. Finally, the specific downregulation of p21(CIP1) and p27(KIP1) further suggests their key role in the maintenance of cell cycle arrest in cardiomyocytes.
 ...
PMID:E2F-1 overexpression in cardiomyocytes induces downregulation of p21CIP1 and p27KIP1 and release of active cyclin-dependent kinases in the presence of insulin-like growth factor I. 1041 94

There is strong evidence that the senescent phenotype, whether induced by telomere shortening, oxidative damage, or oncogenic stimuli, is an important tumor suppressive mechanism. The melanocyte is a cell of neural crest origin that produces the pigment melanin and can develop into malignant melanomas. To understand how malignant cells escape senescence, it is first crucial to define what genes control senescence in the normal cell. Prolonged exposure to high levels of cAMP results in accumulation of melanin and terminal differentiation of human melanocytes. Here we present evidence that activation of a cAMP pathway correlates with multiple cellular changes in these cells: (1) increased expression of the transcription factor microphthalmia; (2) increased melanogenesis; (3) increased association of the cyclin-dependent kinase inhibitors (CDK-Is) p27(KIP1) and p16(INK4) with CDK2 and CDK4, respectively; (4) failure to phosphorylate the retinoblastoma protein (pRB); (5) decreased expression of E2F1, E2F2, and E2F4 proteins; (6) loss of E2F DNA-binding activity; and (7) phenotypic changes characteristic of senescent cells. Senescent melanocytes have potent E2F inhibitory activity, because extracts from these cells completely abolished E2F DNA-binding activity that was present in extracts from the early proliferative phase. We propose that increased activity of the CDK-Is p27 and p16 and loss of E2F activity in human melanocytes characterize a senescence program activated by the cAMP pathway. Disruption of cAMP-mediated and melanogenesis-induced senescence may cause immortalization of human melanocytes, an early step in the development of melanomas.
 ...
PMID:Activation of a cAMP pathway and induction of melanogenesis correlate with association of p16(INK4) and p27(KIP1) to CDKs, loss of E2F-binding activity, and premature senescence of human melanocytes. 1058 80

Transforming growth factor beta (TGF-beta)-mediated G(1) arrest previously has been shown to specifically target inactivation of cyclin D:cyclin-dependent kinase (Cdk) 4/6 complexes. We report here that TGF-beta-treated human HepG2 hepatocellular carcinoma cells arrest in G(1), but retain continued cyclin D:Cdk4/6 activity and active, hypophosphorylated retinoblastoma tumor suppressor protein. Consistent with this observation, TGF-beta-treated cells failed to induce p15(INK4b), down-regulate CDC25A, or increase levels of p21(CIP1), p27(KIP1), and p57(KIP2). However, TGF-beta treatment resulted in the specific inactivation of cyclin E:Cdk2 complexes caused by absence of the activating Thr(160) phosphorylation on Cdk2. Whole-cell lysates from TGF-beta-treated cells showed inhibition of Cdk2 Thr(160) Cdk activating kinase (CAK) activity; however, cyclin H:Cdk7 activity, a previously assumed mammalian CAK, was not altered. Saccharomyces cerevisiae contains a genetically and biochemically proven CAK gene, CAK1, that encodes a monomeric 44-kDa Cak1p protein unrelated to Cdk7. Anti-Cak1p antibodies cross-reacted with a 45-kDa human protein with CAK activity that was specifically down-regulated in response to TGF-beta treatment. Taken together, these observations demonstrate that TGF-beta signaling mediates a G(1) arrest in HepG2 cells by targeting Cdk2 CAK and suggests the presence of at least two mammalian CAKs: one specific for Cdk2 and one for Cdk4/6.
 ...
PMID:Transforming growth factor beta targeted inactivation of cyclin E:cyclin-dependent kinase 2 (Cdk2) complexes by inhibition of Cdk2 activating kinase activity. 1061 20

We evaluated the effect of beta1-integrin receptor engagement on the expression and activity of cell cycle regulatory proteins in CD34(+) cells under conditions that mimic the steady-state marrow microenvironment and in the presence of supraphysiological concentrations of interleukin-3 (IL3) and stem cell factor (SCF). Adhesion of CD34(+) progenitors to fibronectin (FN) was similar whether IL3 or SCF was present or absent. Engagement of beta1-integrins blocked S-phase entry of CD34(+) cells in the absence of IL3 or SCF, whereas addition of 10 ng/mL IL3 or SCF prevented such a block in S-phase entry. In the absence of IL3 or SCF, cyclin-E levels were significantly lower and p27(KIP1) levels significantly higher in FN-adherent than in FN-nonadherent cells, or than in poly-L-lysine (PLL)-adherent or (PLL)-nonadherent cells. Cyclin-dependent-kinase (cdk)-2 activity was decreased and levels of cyclin-E-cdk2 complexes were lower in FN-adherent than in PLL-adherent cells. In contrast, cyclin-E and p27(KIP1) protein levels and cdk2 activity in cells adherent to FN in the presence of IL3 or SCF were similar to those in PLL-adherent and FN-nonadherent or PLL-nonadherent cells. In conclusion, under physiological cytokine conditions, integrin engagement prevents S-phase entrance of CD34(+) cells, which is associated with elevated levels of the contact-dependent cyclin kinase inhibitor p27(KIP1). Supraphysiological concentrations of IL3 or SCF prevent p27(KIP1) elevation and override the integrin-mediated inhibition of entry into S phase.
 ...
PMID:Opposing effects of engagement of integrins and stimulation of cytokine receptors on cell cycle progression of normal human hematopoietic progenitors. 1064 95

14-3-3 sigma, implicated in cell cycle arrest by p53, was cloned by expression cloning through cyclin-dependent kinase 2 (CDK2) association. 14-3-3 sigma shares cyclin-CDK2 binding motifs with different cell cycle regulators, including p107, p130, p21(CIP1), p27(KIP1), and p57(KIP2), and is associated with cyclin.CDK complexes in vitro and in vivo. Overexpression of 14-3-3 sigma obstructs cell cycle entry by inhibiting cyclin-CDK activity in many breast cancer cell lines. Overexpression of 14-3-3 sigma can also inhibit cell proliferation and prevent anchorage-independent growth of these cell lines. These findings define 14-3-3 sigma as a negative regulator of the cell cycle progression and suggest that it has an important function in preventing breast tumor cell growth.
 ...
PMID:Association of the cyclin-dependent kinases and 14-3-3 sigma negatively regulates cell cycle progression. 1076 98

Acquisition of an immortal phenotype by circumvention of the normal senescence program can be an important step in tumor development and progression. The regulation of life-span checkpoints is complex and abrogation of these processes can occur at different levels. To better understand these mechanisms in long-term cultured lymphocytes we have characterized two human long-term cultured IL-2-dependent T cell lines regarding telomere length, telomerase activity, and the expression of selected cell cycle regulators (pRb, p53, cyclin E, cyclin D1, cyclin D2, cyclin D3, cdk4, p16(INK4a), p21(WAF1), p27(KIP1), c-myc, bcl-2, and NPAT). We compared these cell lines with a primary T lymphoblast population with a limited life span from the same donor. Both T cell lines with extraordinary growth capacity showed telomere length stabilization, high telomerase activity and demonstrated wild-type pattern of pRb and p53 but strong p16(INK4a) protein expression. The growth inhibitory activity of p16(INK4a) seemed to be abrogated by enhanced expression of cyclin D2, cdk4, and c-myc in one T cell line and overexpression of cyclin E in the second T cell line.
 ...
PMID:Long-term cultured IL-2-dependent T cell lines demonstrate p16(INK4a) overexpression, normal pRb/p53, and upregulation of cyclins E or D2. 1083 57

Apoptosis of SK-HEP-1 human hepatoma cells induced by treatment with ginsenoside Rh2 (G-Rh2) is associated with rapid and selective activation of cyclin A-associated cyclin-dependent kinase 2 (Cdk2). Here, we show that in apoptotic cells, the Cdk inhibitory protein p21(WAF1/CIP1), which is associated with the cyclin A-Cdk2 complex, undergoes selective proteolytic cleavage. In contrast, another Cdk inhibitory protein, p27(KIP1), which is associated with cyclin A-Cdk2 and cyclin E-Cdk2 complexes, remained unaltered during apoptosis. Ectopic overexpression of p21(WAF1/CIP1) suppressed apoptosis as well as cyclin A-Cdk2 activity induced by treatment of SK-HEP-1 cells with G-Rh2. The suppressive effects of p21(WAF1/CIP1) were much higher in the cells transfected with p21D112N, an expression vector that encodes a p21(WAF1/CIP1) mutant resistant to caspase 3 cleavage. Overexpression of cyclin A in SK-HEP-1 cells dramatically up-regulated cyclin A-Cdk2 activity and accordingly enhances apoptosis induced by treatment with G-Rh2. These up-regulating effects were blocked by coexpression of a dominant negative allele of cdk2. Furthermore, olomoucine, a specific inhibitor of Cdks, also blocked G-Rh2-induced apoptosis. These data suggest that the induction of apoptosis in human hepatoma cells treated with G-Rh2 occurs by a mechanism that involves the activation of cyclin A-Cdk2 by caspase 3-mediated cleavage of p21(WAF1/CIP1).
 ...
PMID:Caspase 3-mediated cleavage of p21WAF1/CIP1 associated with the cyclin A-cyclin-dependent kinase 2 complex is a prerequisite for apoptosis in SK-HEP-1 cells. 1088 82

Transforming growth factor beta1 (TGFbeta1) induces growth arrest in many cell types, including B lymphocytes. We examined the effect of TGF on cell cycle progression of a non-Hodgkin lymphoma cell line of follicular lymphoma subtype (FL). After 48 h of TGFbeta1 (10 ng/ml) treatment, a significantly increased number of DoHH2 cells was retained in G(0)/G(1) phase. We examined the level of cell cycle components, cyclins, cyclin-dependent kinases (cdk), and their inhibitors. We found that the expression of cyclin A and p21(WAF1) molecules was primarily modulated by TGFbeta1 treatment while the expression of other regulatory components, like cyclins D, cyclin E, cdk2, cdk4, and cdk6 or p15(INK4B), p16(INK4A), and p27(KIP1) was not significantly affected. We further examined expression and activity of CREB/ATF family members to examine their roles in cyclin A inhibition. The binding activity of CREB-1 and ATF-2 to the CRE region of the cyclin A promoter was almost completely abolished due to the treatment. The total level of CREB-1, ATF-2, and ATF-3 was notably reduced. Moreover, CREB-1 was dephosphorylated due to the treatment as revealed by immunoblotting. We assume that down-regulation of cyclin A was mediated by the absence of CREB/ATF activation dimers. The profound effect on the ATF family of transcription factors indicates the complexity of TGFbeta1 action on FL B malignant cells.
 ...
PMID:Cyclin A down-regulation in TGFbeta1-arrested follicular lymphoma cells. 1108 95


<< Previous 1 2 3 4 5 6 7 Next >>