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

The growth suppressing activity of the retinoblastoma suspectibility gene product, pRb, is down regulated by cyclin-dependent kinases 4 and 6 (CDK4 and CDK6) whose kinase activity is negatively regulated by CDK inhibitors of the p16 family. We have examined the genomic status of two recently isolated p16-related CDK inhibitors, p15 and p18, in 15 normal and 73 tumor-derived cell lines established from 23 different tissues, as well as 26 invasive primary breast cancers and 20 acute myelogenous leukemias. p15 was found to be homozygously deleted in 22% of the tumor derived cell lines, but no point mutations were found in either the cultured cells or the two types of primary tumors. With the exception of one breast cancer cell line, no deletions or mutations were found in the p18 gene in either cultured cell lines or primary tumors. These results indicate that mutation of the p18 gene occurs rarely in human tumors. Thus, while they share a very similar biochemical mechanism of inhibiting the kinase activity of CDK4 and CDK6, members of the p16 gene family play different roles in controlling cell proliferation and suppressing tumor growth.
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PMID:Mutational analysis of the p16 family cyclin-dependent kinase inhibitors p15INK4b and p18INK4c in tumor-derived cell lines and primary tumors. 857 Feb 24

Many neurons in the developing nervous system undergo programmed cell death, or apoptosis. However, the molecular mechanism underlying this phenomenon is largely unknown. In the present report, we present evidence that the cell cycle regulator cyclin D1 is involved in the regulation of neuronal cell death. During neuronal apoptosis, cyclin D1-dependent kinase activity is stimulated, due to an increase in cyclin D1 levels. Moreover, artificial elevation of cyclin D1 levels is sufficient to induce apoptosis, even in non-neural cell types. Cyclin D1-induced apoptosis, like neuronal apoptosis, can be inhibited by 21 kDa E1B, Bcl2 and pRb, but not by 55 kDa E1B. Most importantly, however, overexpression of the cyclin D-dependent kinase inhibitor p16INK4 protects neurons from apoptotic cell death, demonstrating that activation of endogenous cyclin D1-dependent kinases is essential during neuronal apoptosis. These data support a model in which neuronal apoptosis results from an aborted attempt to activate the cell cycle in terminally differentiated neurons.
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PMID:Cyclin D1 is an essential mediator of apoptotic neuronal cell death. 859 5

Biopsies from 61 sporadic metastatic malignant melanomas and five melanoma cell lines were examined for homozygous deletions and mutations in the CDKN2 gene (p16). As the p16 protein is involved in a cell cycle regulatory pathway consisting of at least pRb, cdk4 and cyclin D1, the tumours were also screened for amplifications of the last two genes. Moreover, the transcript levels of the genes were determined and the results compared with the immunohistochemically assessed expression of pRb. Altogether, homozygous deletions of CDKN2 were found in seven tumours (11%) and two of five cell lines, whereas a mutation was detected in only one biopsy, indicating that in sporadic melanomas the former mechanism is predominant for inactivating this gene. Notably, in total 59% of the metastatic lesions lacked detectable expression of p16 mRNA, whereas all the biopsies were found to express pRb. In accordance with the postulated negative feedback loop between p16 and pRb, one melanoma cell line showed overexpression of CDKN2 mRNA together with very low levels of the Rb protein. Amplification of the other two genes may not be important in the tumorigenesis of melanomas, as only one CDK4 and no CCND1 amplification was observed. However, highly elevated CDK4 mRNA levels, compared with that seen in a panel of normal tissues, were observed in 76% of the tumours, accompanied in 71% of the cases by high expression of the CCND1 cyclin activator. Although a low frequency of CDKN2 DNA aberrations was observed, the high number of tumours that lacked CDKN2 expression but showed overexpression of CDK4 and/or CCND1, suggest that functional inactivation of pRb through this pathway may be involved in the development or progression of sporadic human melanomas.
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PMID:Involvement of the pRb/p16/cdk4/cyclin D1 pathway in the tumorigenesis of sporadic malignant melanomas. 861 25

Cells which are highly proliferative typically lack expression of differentiated, lineage-specific characteristics. Id2, a member of the helix-loop-helix (HLH) protein family known to inhibit cell differentiation, binds to the retinoblastoma protein (pRb) and abolishes its growth-suppressing activity. We found that Id2 but not Id1 or Id3 was able to bind in vitro not only pRb but also the related proteins p107 and p130. Also, an association between Id2 and p107 or p130 was observed in vivo in transiently transfected Saos-2 cells. In agreement with these results, expression of Id1 or Id3 did not affect the block of cell cycle progression mediated by pRb. Conversely, expression of Id2 specifically reversed the cell cycle arrest induced by each of the three members of the pRb family. Furthermore, the growth-suppressive activities of cyclin-dependent kinase inhibitors p16 and p21 were efficiently antagonized by high levels of Id2 but not by Id1 Id3. Consistent with the role of p16 as a selective inhibitor of pRb and pRb-related protein kinase activity, p16-imposed cell cycle arrest was completely abolished by Id2. Only a partial reversal of p21-induced growth suppression was observed, which correlated with the presence of a functional pRb. We also documented decreased levels of cyclin D1 protein and mRNA and the loss of cyclin D1-cdk4 complexes in cells constitutively expressing Id2. These data provide evidence for important Id2-mediated alterations in cell cycle components normally involved in the regulatory events of cell cycle progression, and they highlight a specific role for Id2 as an antagonist of multiple tumor suppressor proteins.
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PMID:Id2 specifically alters regulation of the cell cycle by tumor suppressor proteins. 864 64

The regulation of the D-type cyclin-dependent kinase (CDK4 and CDK6) activity appears to be the key step in the progression of eukaryotic cells through the G1 cell cycle phase. One of the mechanisms involved in this process is the binding of some small proteic inhibitors, with a molecular mass ranging between 14 and 20 kDa, to these CDKs. We have evaluated the amount of two such inhibitors, namely p16(INK4) and p18, in normal and transformed cells, as well as the biochemical features of the macromolecular complexes containing these proteins. The results obtained indicated that (i) p18 gene expression, unlike p16(INK4) gene, is not regulated by pRb status, (ii) no evident relationship exists between the expression of p16(INK4) and p18 genes, (iii) significant amounts of the two proteins are not bound to CDKs but occur as free molecules, (iv) each inhibitor forms a complex with the CDK protein with a 1:1 stoichiometry, and (v) a competition exists between cyclin D and the inhibitor protein toward the CDK protein resulting in the absence of detectable cellular free kinase. Moreover, employing the human native partially purified p16(INK4)or the pure recombinant protein, we have been able to demonstrate in vitro the dissociation of CDK4-cyclin D1 complex and the formation of CDK4-p16(INK4) bimolecular complex. Our findings suggest that during the cell division cycle the members of the p16(INK4) protein family and cyclin Ds compete for binding to CDK4/CDK6 and that their quantitative ratio is essential for G1 --> S transition.
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PMID:Biochemical characterization of p16INK4- and p18-containing complexes in human cell lines. 866 31

A protein kinase inhibitor K252a suppressed the growth of HuH7 hepatoma cells and the hyperphosphorylation of retinoblastoma protein (pRb) at late G1 phase of cell cycle. However, K252a treatment did not alter the levels of cyclin D1, cyclin E, cyclin A and Cdk2 protein bound to cyclin E or cyclin A. Therefore, the K252a inhibition of pRb phosphorylation is considered to be brought about probably by inhibiting the action of Cdk-cyclin complex rather than by changing its cellular level. These results also suggest that K252a is a useful tool for investigating the mechanism of phosphorylation of pRb mediated by Cdk-cyclin.
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PMID:K252a inhibits the phosphorylation of pRb without changing the levels of G1 cyclins and Cdk2 protein in human hepatoma cells. 869 9

The expression of the CDK inhibitor (CDI) genes p15(INK4B), p16(INK4A), p18 and p21Cip1 was examined in immortalized, non-tumorigenic cell lines derived from human breast epithelium, and in breast carcinoma derived lines. An increase in p16 expression, suggesting loss of pRb function, was recorded in two immortalized lines, and complete absence of p16 mRNA was observed in the third. In contrast, high levels of p21Cip1 mRNA were found in two immortalized lines. In addition to differences in p16 and p21Cipl, variations in the expression of p15 and p18 mRNA were observed between different cell lines. Immortalized A1N4 and HBL100 cells, as well as ER+, MCF-7 carcinoma cells, expressed high levels of p15 mRNA. A1N4, HBL100 cells and highly malignant ER MDA-MB-231 cells expressed high levels of p18 mRNA. Inhibition by genistein indicated that p18 mRNA expression was dependent on cellular tyrosine kinases in these cells. We conclude that the pattern of p15 and p18 mRNA expression was distinct from that of p16 and p21Cip1, suggesting different modes of regulation.
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PMID:Expression of CDK inhibitor genes in immortalized and carcinoma derived breast cell lines. 871 23

Rat fibroblasts transformed by a temperature-sensitive mutant of murine p53 undergo a reversible growth arrest in G1 at 32.5 degrees C, the temperature at which p53 adopts a wild-type conformation. The arrested cells contain inactive cyclin-dependent kinase 2 (cdk2) despite the presence of high levels of cyclin E and cdk-activating kinase activity. This is due in part to p53-dependent expression of the p2l cdk inhibitor. Upon shift to 39 degrees C, wild-type p53 is lost and cdk2 activation and pRb phosphorylation occur concomitantly with loss of p2l. This p53-mediated growth arrest can be abrogated by overexpression of cdk4 and cdk6 but not cdk2 or cyclins, leading to continuous proliferation of transfected cells in the presence of wild-type p53 and p2l. Kinase-inactive counterparts of cdk4 and cdk6 also rescue these cells from growth arrest, implicating a noncatalytic role for cdk4 and cdk6 in this resistance to p53-mediated growth arrest. Aberrant expression of these cell cycle kinases may thus result in an oncogenic interference with inhibitors of cell cycle progression.
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PMID:Inhibition of p53-mediated growth arrest by overexpression of cyclin-dependent kinases. 875 45

Terminally differentiated cells are characterized by permanent withdrawal from the cell cycle; they do not enter S phase even when stimulated by growth factors or retroviral oncogenes. We have shown, however, that the adenovirus E1A oncogene can reactivate the cell cycle in terminally differentiated cells. In this report, we describe the molecular events triggered by E1A in terminally differentiated skeletal muscle cells. We found that in myotubes infected with the adenovirus mutant dl520, 12S E1A bypasses the early G1 phase and activates the expression of late-G1 genes, such as the cyclin E and cyclin A genes, cdk2, PCNA, and B-myb. Of these, the cyclin E gene and cdk2 were significantly overexpressed in comparison with levels in proliferating, undifferentiated myoblasts. p130 and pRb were phosphorylated before the infected myotubes entered S phase, despite the high expression of the cyclin-dependent kinase inhibitor p21, and E2F was released. Our results suggest that one of the mechanisms that E1A uses to overcome the proliferative block of terminally differentiated cells involves coordinated overexpression of cyclin E and cdk2. Following E1A expression, the myogenic transcription factors MyoD and myogenin and the muscle-specific structural genes encoding muscle creatine kinase and myosin heavy chain were downregulated. The muscle regulatory factors were also silenced in myotubes infected with adenovirus E1A mutants incapable of reactivating the cell cycle in terminally differentiated muscle cells. Thus, the suppression of the differentiation program is not a consequence of cell cycle reactivation in myotubes, and it is induced by an independent mechanism. Our results show that E1A reactivates the cell cycle and suppresses tissue-specific gene expression in terminally differentiated muscle cells, thus causing dedifferentiation.
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PMID:Expression of E1A in terminally differentiated muscle cells reactivates the cell cycle and suppresses tissue-specific genes by separable mechanisms. 881 42

The cyclin-dependent kinases cdk2 and cdk3 are required for the G1-S transition in mammalian cells. Here we show that G1 arrest induced by the corresponding dominant-negative mutants of these enzymes, cdk2dn or cdk3dn, is resistant to the action of SV40 T antigen (T). In the presence of cdk2dn, T released active E2F from negative control by pRb and its related family members (pocket proteins) but failed to induce S-phase. Therefore, among other targets, cdk2 also phosphorylates nonpocket protein substrates in promoting S-phase entry, and T does not mimic all cdk2 functions. In the presence of cdk3dn, however, T failed to induce cell cycle progression or stimulate E2F-dependent transcription activity. Dominant-negative cdk3 inhibited E2F-1, E2F-2, and, less significantly, E2F-3, but not E2F-4 transcription activity. The inhibition occurred in a pRb-independent manner and did not affect the DNA-binding capacity of the transcription factor. Cdk3 bound specifically to E2F-1/DP-1 complexes in vivo, most likely through DP-1. Thus, cdk3 function contributes to the activation of E2F-1, E2F-2, and partially E2F-3 and, thereby, participates in the process of S-phase entry.
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PMID:Differential effects of cdk2 and cdk3 on the control of pRb and E2F function during G1 exit. 884 21


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