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)

Chromosome band 9p21 is deleted frequently in non-small cell lung carcinoma (NSCLC), and the p15 and p16 cyclin-dependent kinase-4 inhibitor genes map within this deletion region. Recent studies demonstrated deletion of p15 and p16 in NSCLC metastases and cell lines, suggesting a role for these genes in NSCLC progression. We now report p15 and p16 copy number, as determined by fluorescence in situ hybridization with a P1 contig, in 18 primary NSCLCs. Codeletion of p15 and p16 was found in 15 of 18 NSCLCs, and 1 of the 3 tumors with normal p15 and p16 copy number had a nonsense mutation in exon 2 of p16. We conclude that p15 and p16 are deleted and/or mutated in most primary NSCLCs. Two observations, however, support the involvement of at least one additional tumor suppressor gene on chromosome 9. These observations are: (a) the large size (> 100 kb) of most NSCLC p15/p16 deletions; and (b) the absence of exon 2 mutations in most retained NSCLC p15 and p16 alleles.
 ...
PMID:Codeletion of p15 and p16 genes in primary non-small cell lung carcinoma. 760 11

G1 progression in mammalian cells requires the activity of the cyclin D-dependent kinases Cdk4 and/or Cdk6 and the cyclin E-dependent kinase Cdk2. Proliferating Mv1Lu mink lung epithelial cells and human keratinocytes contain high levels of the universal Cdk inhibitor p27Kip1 distributed in complexes with Cdk2, Cdk4, and Cdk6. Addition of the antimitogenic cytokine transforming growth factor-beta (TGF-beta) elevates expression of the Cdk4/6-specific inhibitor p15Ink4B and induces the release of p27 from Cdk4 and Cdk6. In Mv1Lu cells, this release of p27 coincides with increased binding of p27 to Cdk2. Recombinant p15 inhibits p27 binding to Cdk4 in vitro, and p15 overexpression induces the transfer of p27 from Cdk4 to Cdk2 in vivo, suggesting that the release of Cdk4-bound p27 in TGF-beta-treated cells is caused by the surge in p15 levels. In keratinocytes, TGF-beta increases not only p15 but also p21Cip1, which binds to Cdk2. These events correlate with Cdk2 inhibition and cell cycle arrest and occur without a loss of G1 Cdk components. The results suggest that TGF-beta induces G1 arrest in these two epithelial cell types by inhibiting various cyclin-Cdk kinases through the cooperative action of an Ink4 Cdk inhibitor and a Cip/Kip Cdk inhibitor. Subsequent to cell cycle arrest, Cdk2 and Cdk4 levels decline as part of a second set of events that may represent a program of cell adaptation to the quiescent state.
 ...
PMID:Kip/Cip and Ink4 Cdk inhibitors cooperate to induce cell cycle arrest in response to TGF-beta. 764 71

Progression through the G1 phase of the cell cycle is regulated in part by the D-type cyclin-dependent kinases, cdk4 and cdk6. Genes encoding two specific inhibitors of these kinases, human p16(INK4a/MTS1) and p15(INK4b/MTS2), map to a region of common cytogenetic abnormalities on chromosome 9p21. The murine cognates of these genes were isolated and identified as mouse p16INK4a and p15INK4b based on their homology to their human counterparts and their selective transcriptional induction by SV40T-antigen and TGF-beta, respectively. Both genes map to position C3-C6 on mouse chromosome 4, in a region syntenic with human chromosome 9p. Amplification of polyadenylated mRNA by polymerase chain reactions revealed no expression of mouse p16INK4a in many normal tissues, whereas p15INK4b was expressed ubiquitously. Like human p16INK4a, mouse p16INK4a binds specifically to cdk4 and cdk6 in vitro and inhibits the phosphorylation of the retinoblastoma protein, pRb, by each of these cyclin D-dependent kinases. In mouse MEL erythroleukemia cells, p16INK4a associates preferentially with cdk6 under conditions where cdk4 and cdk6 are coexpressed at equivalent levels. Expression vectors encoding human or mouse p16INK4a caused G1 phase arrest in NIH3T3 fibroblasts, and cyclin D1- and cdk4-dependent pRb kinase activities were inhibited in the p16INK4a-arrested cells.
 ...
PMID:Cloning and characterization of murine p16INK4a and p15INK4b genes. 765 26

The D-type cyclin-dependent kinases CDK4 and CDK6 are complexed with many small cellular proteins (p14, p15, p16, p18, and p20). We have isolated cDNA sequences corresponding to the MTS2 genomic fragment that encodes the CDK4- and CDK6-associated p14 protein. By use of a yeast interaction screen to search for CDK6-interacting proteins, we have also identified an 18-kD human protein, p18, that is a homolog of the cyclin D-CDK4 inhibitors p16 (INK4A/MTS1) and p14 (MTS2/INK4B). Both in vivo and in vitro, p18 interacts strongly with CDK6, weakly with CDK4, and exhibits no detectable interaction with the other known CDKs. Recombinant p18 inhibits the kinase activity of cyclin D-CDK6. Distinct from the p21/p27 family of CDK inhibitors that form ternary complexes with cyclin-CDKs, only binary complexes of p14, p16, and p18 were found in association with CDK4 and/or CDK6. Ectopic expression of p18 or p16 suppresses cell growth with a correlated dependence on endogenous wild-type pRb.
 ...
PMID:Growth suppression by p18, a p16INK4/MTS1- and p14INK4B/MTS2-related CDK6 inhibitor, correlates with wild-type pRb function. 800 16

The genes MTS1/p16 and MTS2/p15 located in 9p21 encoding cyclin-dependent kinase-4 inhibitors are homozygously deleted in a number of different tumour cell lines. By PCR analysis of 30 cell lines, including 10 acute lymphoblastic leukaemia (ALL) and 20 lymphoma cell lines, we found homozygous deletions of at least one locus in 11 (37%) cell lines. MTS1-specific sequences were deleted in 70% of ALL (reaching 86% in T-cell ALL) but in none of the non-Hodgkin's lymphoma (NHL) cell lines. MTS2-specific sequences were deleted in 40% of ALL and 17% of NHL cell lines. We observed a higher frequency of MTS1 deletions in ALL than in NHL (P < 0.001) and in T-cell neoplasms compared to B-cell neoplasms (67% v 6%; P = 0.001). In ALL-derived cell lines deletions of the MTS2 gene only occurred in cases with MTS1 deletions but in NHL only in cases without MTS1 deletions.
 ...
PMID:Homozygous loss of the MTS1/p16 and MTS2/p15 genes in lymphoma and lymphoblastic leukaemia cell lines. 854 74

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.
 ...
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

p18 is a recently described cyclin-dependent kinase inhibitor (CDK-I) wih homology to p16 and p15. The latter two CDK-Is have been implicated as possible tumor suppressor genes in a wide variety of human tumors, including hematological malignancies. Because of p18's structural and functional homology to p16 and p15, we hypothesized that it may also function as a tumor suppressor gene in some lymphoid malignancies. To explore this possibility we examined 81 primary lymphoid tumors for deletion and mutation p18. The primary tumors included 40 T cell malignancies and 41 B cell malignancies. None of the lymphoid tumors studied possessed deletions of p18, including a group of lymphoblastic lymphomas which we previously reported to have deletions of p16 and p15. PCR-SSCP analysis of the p18 gene identified a single polymorphism of codon 114, but failed to demonstrate mutations in any of the lymphoid tumors. These results do not support a role for p18 in the pathogenesis of the lymphoid neoplasms studied.
 ...
PMID:Absence of p18 mutations or deletions in lymphoid malignancies. 863 48

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.
 ...
PMID:Expression of CDK inhibitor genes in immortalized and carcinoma derived breast cell lines. 871 23

In summary, TGF-beta induces cell cycle arrest, at least in part, through down-regulation of cdk4 levels and inhibition of cdk2 activity. Thus both of the kinases thought to be responsible for phosphorylation and inactivation of RB in mid to late G1 are affected by the cytokine. Inhibition of cdk4 synthesis occurs at the translational level, is p53 dependent, and requires the 5' UTR of cdk4. David Beach's laboratory has found that TGF-beta also causes the induction of the cdk4-specific inhibitor p15 (a p16 family member). Thus TGF-beta uses two pathways to regulate cdk4 function: decreasing its expression and inhibiting its function. Mutant p53 confers resistance to TGF-beta by preventing cdk4 down-regulation and overcoming the inhibition of cdk2 activity. Work from the laboratories of both Massague and Roberts has shown that the inhibition of cdk2 brought about by TGF-beta is caused by the cdk inhibitor p27.
 ...
PMID:p53-dependent repression of cdk4 synthesis in transforming growth factor-beta-induced G1 cell cycle arrest. 883 83

Rearrangement and overexpression of the PRAD1/cyclin D1 oncogene, a cell cycle regulator, have been implicated in the pathogenesis of a subset of parathyroid adenomas. Recently, two cell cycle regulators that inhibit the cyclin D1-associated kinases cdk4 and cdk6 have been identified: p16 and p15, the products of the INK4A (also known as CDKN2, MTS1) and INK4B (also known as MTS2) putative tumor suppressor genes located on 9p21. Because inactivation of the p16 or p15 genes might be expected to result in oncogenic consequences similar to those from cyclin D1 overexpression, we examined 25 parathyroid adenomas for 1) allelic loss of polymorphic DNA loci on chromosome arm 9p, 2) homozygous deletions of the p16 and p15 genes by Southern blot analysis, and 3) mutations of the p16 and p15 genes by single strand conformational polymorphism analysis. Heterozygous allelic loss at 9p was observed in 4 of 25 adenomas (16%); their smallest shared region of deletion was 9p21-pter, which includes both the p16 and p15 genes. However, single strand conformational polymorphism analysis of all 3 exons of the p16 gene and both exons of the p15 gene failed to demonstrate mutation in any of the 25 cases, and homozygous deletions of the p16 and p15 genes, which are present in some human cancers, were not found in any parathyroid tumors. These observations indicate that inactivating mutations or homozygous deletions of the p16 and p15 genes occur uncommonly, if ever, in parathyroid adenomas; however, loss of a different tumor suppressor gene (or genes) on 9p appears to contribute to the pathogenesis of a significant percentage of these tumors.
 ...
PMID:Loss of chromosome arm 9p DNA and analysis of the p16 and p15 cyclin-dependent kinase inhibitor genes in human parathyroid adenomas. 885 19


1 2 3 4 5 6 7 8 9 10 Next >>