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)

Approximately 8-12% of melanoma is inherited in an autosomal dominant fashion with variable penetrance. A chromosome 9p21 locus has been linked to this disease in 50-80% of affected families. CDKN2A (also known as P16, INK4, p16INK4A and MTS1) is allelic to this locus and encodes a cdk4/cdk6 kinase inhibitor that constrains cells from progressing through the G1 restriction point. Although germline CDKN2A coding mutations cosegregate with melanoma in 25-60% of families predisposed to the disease, there remains a number of mutation-negative families that demonstrate linkage of inherited melanoma to 9p21 markers. We show here that a subset of these kindreds possess a G-->T transversion at base -34 of CDKN2A, designated G-34T. This mutation gives rise to a novel AUG translation initiation codon that decreases translation from the wild-type AUG. The G-34T mutation is not seen in controls, segregates with melanoma in families and, on the basis of haplotyping studies, probably arose from a common founder in the United Kingdom. Characterization of this and other CDKN2A non-coding mutations should have an impact on current efforts to identify susceptible melanoma-prone families and individuals.
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PMID:Mutation of the CDKN2A 5' UTR creates an aberrant initiation codon and predisposes to melanoma. 991 6

p16INK4a and p15INK4b genes, which encode two functionally related CDK inhibitors, recently emerged as candidate tumor suppressor genes since they were both localized to 9p21, which frequently undergoes hemizygous and homozygous deletion in a variety of tumor types. To determine the mode of inactivation of these two genes in human esophageal squamous cell carcinoma (ESCC), we performed multiple molecular analyses in 60 ESCC specimens from Linxian, China using DNA methylation assay, LOH analysis, deletion screening and SSCP-sequencing. We observed that p16INK4a inactivation was predominantly associated with aberrant methylation in the CpG island of its promoter region, whereas p15INK4b frequently had homozygous deletions. Compared with aberrant methylation, which occurred in 17 of 34 cases, homozygous deletion of p16INK4a and LOH at its nearby D9S942 microsatellite marker were observed at a much lower frequency (17%). Intragenic mutation in p16INK4a gene was rare. In contrast, homozygous deletion in p15INK4b and LOH at the nearby D9S171 marker were observed at frequencies of 35 and 47%, respectively, and the two events were significantly associated with each other. On the other hand, aberrant methylation of p15INK4b was relatively infrequent (6/34) and occurred concomitantly with p16INK4a methylation. Among the 60 cases, only four contained a continuous homozygous deletion spanning both p15INK4b and p16INK4a. Six cases were exclusively deleted at p16INK4a and 17 exclusively deleted at p15INK4b. LOH at D9S942 and D9S171 was also found to be mutually exclusive. Our results suggest that the alteration mode at 9p21 was not uniform, and the two genes were inactivated by distinct mechanisms. Altogether, 68% of the samples harbor at least one type of alteration in p16INK4a gene and 50% of the samples were altered in p15INK4b gene, indicating that they are the frequent inactivating targets during ESCC development.
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PMID:Aberrant methylation of p16INK4a and deletion of p15INK4b are frequent events in human esophageal cancer in Linxian, China. 993 53

Ras mutations are common in lung adenocarcinomas and squamous-cell cancers, which are non-small-cell lung cancers (NSCLCs). However, small-cell lung cancers (SCLCs) rarely have ras mutations, suggesting that ras activation may not confer a growth advantage in these cells. In one SCLC cell line DMS53, activated ras expression induced increased neuroendocrine differentiation and decreased cell proliferation. We show here that DMS53 cells undergo differentiation and G1-specific growth arrest in response to ras/raf/ mitogen-activated protein kinase kinase (MEK)/mitogen-activated protein kinase (MAPK) pathway activation. To assess the consequences of activating the raf/MEK/MAPK pathway downstream of ras, we transfected a DMS53 cell line with DeltaRaf-1:ER, an activatable form of c-raf-1. DeltaRaf-1:ER activation suppressed cell proliferation and cloning on soft agar by 90% without evidence of apoptosis. Cell cycle analysis showed a reduced proportion of cells in S phase, and was associated with induction of the cyclin-dependent kinase (cdk) inhibitor p16(INK4). Expression of the cell cycle-specific proteins pRb, Rb2/p130, p107, cyclin A, cdc-2, and E2F-1 was decreased after DeltaRaf-1:ER activation in DMS53 cells. The activity cdk4 and cdk2 was also reduced, as consistent with cell cycle arrest in cells with activated DeltaRaf-1:ER cells. In addition, DeltaRaf-1:ER reduced the expression of neuroendocrine markers, gastrin releasing peptide, and ret gene in DMS53:DeltaRaf-1:ER cells. These results provide further evidence that activation of the raf/MEK/ MAPK signaling pathway, which is associated with transformation in many circumstances, can reduce the growth of SCLC cells, and suggest that activation of this pathway might be clinically efficacious in some settings.
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PMID:Raf-1 causes growth suppression and alteration of neuroendocrine markers in DMS53 human small-cell lung cancer cells. 1010 Sep 84

The CDKN2A gene encodes the cell cycle inhibitor p16/ INK4A, which is involved in familial cutaneous melanoma. We have studied five Swedish familial melanoma kindreds characterized by germline mutations in CDKN2A and dysplastic naevus syndrome (DNS). We found significant correlations between germline CDKN2A mutations and melanoma and between DNS phenotype and melanoma, respectively. There was also a correlation between mutation status and the presence of DNS. In CDKN2A mutation carriers, all cases of early-onset melanoma occurred in DNS individuals, and the mean age at melanoma diagnosis was significantly lower in individuals with DNS than in those without a confirmed DNS phenotype. In one family where the proband had a P48L mutation in CDKN2A exon 1, the DNS phenotype was studied in detail. In vitro binding experiments established that the P48L mutant protein does not bind to cdk4 or cdk6 and thus is functionally abnormal. Furthermore, we demonstrated loss of heterozygosity at markers on chromosome 9p flanking the CDKN2A locus in a primary melanoma and a metastasis from the proband. Our results are consistent with the hypothesis that germline CDKN2A mutations and DNS both contribute to the predisposition to melanoma and may lead to the development of early-onset melanoma when present in the same individual.
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PMID:Melanoma development in relation to non-functional p16/INK4A protein and dysplastic naevus syndrome in Swedish melanoma kindreds. 1033 31

Progression of cells through the G1 phase of the cell cycle requires cyclin D:Cdk4/6 and cyclin E:Cdk2 complexes; however, the duration and ordering of these complexes remain unclear. To address this, we synthesized a peptidyl mimetic of the Cdk4/6 inhibitor, p16INK4a that contained an NH2-terminal TAT protein transduction domain. Transduction of TAT-p16 wild-type peptides into cells resulted in the loss of active, hypophosphorylated pRb and elicited an early G1 cell cycle arrest, provided cyclin E:Cdk2 complexes were inactive. We conclude that cyclin D:Cdk4/6 activity is required for early G1 phase cell cycle progression up to, but not beyond, activation of cyclin E:Cdk2 complexes at the restriction point and is thus nonredundant with cyclin E:Cdk2 in late G1.
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PMID:Transduced p16INK4a peptides inhibit hypophosphorylation of the retinoblastoma protein and cell cycle progression prior to activation of Cdk2 complexes in late G1. 1036 76

The cyclin-dependent kinase inhibitor 2a (Cdkn2a) locus encodes two distinct tumor suppressors, p16INK4a and p19ARF, whose functions interrelate in the regulation of cell proliferation as key components of the retinoblastoma and p53 pathways, respectively. In many types of cancer, alterations of Cdkn2a abrogate the functions of both suppressors, implying that both are integral to the genesis of certain cancer types. While this has been observed in mouse lung adenocarcinogenesis, recent observations also suggested that naturally occurring variation at the Cdkn2a locus is probably operative in the development of these tumors. Firstly, two common haplotypes of mouse Cdkn2a have been identified, each of which encodes cosegregating variants of p16INK4a and p19ARF. The p16INK4a variants differ at amino acids 18 (histidine or proline) and 51 (valine or isoleucine), whereas the p19ARF variants differ only at amino acid 72 (histidine or arginine). Secondly, genetic resistance to lung tumor formation appears to segregate with one particular haplotype, which also is deleted preferentially in lung adenocarcinomas of Cdkn2a heterozygous mice. Here we attempt to explain these observations and to characterize further the roles of p16INK4 and p19ARF in mouse lung tumorigenesis by examining the function and expression of each of the variants of Cdkn2a. Functional analysis showed that the proline 18/isoleucine 51 p16INK4a variant was diminished in cdk6 binding, cdk6 inhibition and NIH/3T3 fibroblast growth suppression compared with the histidine 18/valine 51 variant, whereas both of the p19ARF variants suppressed growth with similar potencies. Also, the different alleles for p16INK4a and p19ARF were transcribed equally in the normal lungs of Cdkn2a heterozygotes, as determined by comparative reverse transcription-polymerase chain reaction-single-stranded conformation polymorphism analysis. These results indicate that strain-specific variation in p16INK4a function is exploited in mouse lung tumorigenesis and strongly implicate a role for p16INK4a in lung cancer predisposition and development.
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PMID:Cdkn2a encodes functional variation of p16INK4a but not p19ARF, which confers selection in mouse lung tumorigenesis. 1036 10

Progression through the G1 phase of the cell cycle is mediated by phosphorylation of the retinoblastoma protein (pRb) resulting in the release of essential transcription factors such as E2F-1. The phosphorylation of pRb is regulated positively by cyclin D1/CDK4 and negatively by CDK inhibitors, such as p16 (CDKN2/MTS-1/INK4A). The p16/cyclin D1/Rb pathway plays a critical role in tumorigenesis and many tumor types display a high frequency of inactivation of at least one component of this pathway. In order to determine the overall contribution of these three components to progression of head and neck squamous cell carcinoma (HNSCC), we examined p16 inactivation, cyclin D1 amplification, and pRb expression in 23 primary HNSCC tumors and five cell lines. p16 inactivation was detected in 19/23 (83%) primary tumors by detailed genetic analysis and was confirmed by immunohistochemistry (IHC). Absence of Rb protein expression indicative of pRb inactivation was identified in 2/23 (9%) tumors. In this set of tumors, there was a perfect inverse correlation between p16 and pRb inactivation. Using fluorescence in situ hybridization (FISH) cyclin D1 amplification was identified in 4/5 (80%) cell lines and 4/11 (36%) primary tumors. However, 2/4 cell lines and all four primary tumors with cyclin D1 amplification contained a concomitant alteration of p16. Therefore 21/ 23 (91%) of primary HNSCC contained at least one alteration in the p16/cyclin D1/Rb pathway. Although p16 and Rb alteration are apparently exclusive, cyclin D1 amplification occurs concomitantly with the loss of p16 suggesting an additional role for this amplification in HNSCC.
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PMID:Cyclin D1 amplification is independent of p16 inactivation in head and neck squamous cell carcinoma. 1037 32

Cyclin-dependent kinase inhibitors are potent suppressors of cell growth and have been proposed as targets for gene replacement therapy in cancer. Expression of either p16INK4a or p21WAF1 protected cells from the cytotoxic effects of the topoisomerase II inhibitor, etoposide. A lower level of p53 was induced in CDK inhibitor-expressing etoposide-exposed cells suggesting that protection may be due to lower levels of DNA damage in the growth arrested cells. Exposure of human osteosarcoma cells to either p16INK4a or p21WAF1 prior to and during etoposide therapy protected cells against etoposide-induced cell death. Infection of the cells by Ad-p16INK4a or Ad-p21WAF1 following exposure to etoposide resulted in loss of the protective effect with evidence of enhanced growth inhibition. The results suggest that the schedule of administration of DNA damaging etoposide chemotherapy and cell cycle inhibitory therapy is a major determinant of the resulting cytotoxicity.
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PMID:The administration schedule of cyclin-dependent kinase inhibitor gene therapy and etoposide chemotherapy is a major determinant of cytotoxicity. 1040 29

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.
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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

The p13suc1/p9CKShs proteins bind tightly to the cyclin-dependent kinases cdk1 and cdk2. The distantly related protein, p15cdk-BP, binds cdk4/6, cdk5 and cdk8. We now show that immobilized p15cdk-BP binds both an HMG-I kinase and a 35-kDa protein that cross-reacts with anti-PSTAIRE antibodies (PSTAIRE is a totally conserved motif located in subdomain III of cdk). This 'cdkX' and the HMG-I kinase also bind to an immobilized inhibitor of cdks (HD). Several properties clearly distinguish cdkX, and its associated HMG-I kinase, from known anti-PSTAIRE cross-reactive cdks: (a) cdkX migrates, in SDS/PAGE, in a position intermediate between prophase phosphorylated cdk1 and metaphase dephosphorylated cdk1; (b) in contrast with cdk1, cdkX and associated HMG-I kinase activity do not decrease following successive depletions on p9CKShs1-sepharose; (c) cdkX and associated HMG-I kinase activity, but not cdk1, decrease following depletions on immobilized inhibitor; (d) cdkX is expressed during the early development of sea urchin embryos; in contrast with cdk1/cyclin B kinase, the p15cdk-BP-bound HMG-I kinase is active throughout the cell cycle; compared with cdk1 it is active later in development; (e) p15cdk-BP-bound HMG-I kinase is essentially insensitive to powerful inhibitors of cdk such as purvalanol, roscovitine, olomoucine, p21cip1 and p16INK4A; HD is only moderately inhibitory. Altogether these results suggest the existence of a new cdk1-related kinase, possibly involved in the regulation of early development. The presence of this kinase in all organisms investigated so far, from plants to mammals, calls for its definitive identification.
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PMID:Characterization of a novel cdk1-related kinase. 1044 73


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