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)

Deletion of 9p21-22 is a common genetic alteration in dysplastic, in situ, and invasive head and neck squamous cell carcinoma (HNSCC). However, a candidate tumor suppressor gene (TSG) at this site has thus far not been identified in HNSCC. We report homozygous deletion of the recently identified multiple tumor suppressor I (MTSI)/cyclin-dependent kinase-4-inhibitor (CDKN2) gene mapped to 9p21, which encodes the p16 protein, a regulator of cyclin-dependent kinase 4, in six of 16 HNSCC cell lines. We also show absence of the CDKN2 mRNA in all cell lines with CDKN2 deletion as well as in an additional two cell lines without deletion. Overall, we have identified 9p abnormalities in 12 of 16 (75%) cell lines, at least nine of which involved CDKN2. We further demonstrate that the CDKN2 deletion in HNSCC is located within a previously described region of allelic loss between D9S171 and IFNW, which spans a 4 cM region of 9p. However, examination of 36 primary tumors revealed genetic alterations in only seven of 36 (19%) tumors. These results suggest that genetic alterations at CDKN2 are frequent in HNSCC cell lines, but the role of this gene in primary tumors is less compelling. CDKN2 does not appear to be the only TSG on 9p21 in HNSCC, and our results suggest that another region of deletion exists proximal to the IFNW locus.
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PMID:Homozygous deletions and loss of expression of the CDKN2 gene occur frequently in head and neck squamous cell carcinoma cell lines but infrequently in primary tumors. 754 12

cdk4-mediated phosphorylation of the retinoblastoma susceptibility protein (Rb) is stimulated by cyclin D1, an oncogene, and inhibited by p16, a candidate tumor suppressor. We examined these proteins in non-small cell lung cancer (NSCLC), which is predominantly Rb positive, and small cell lung cancer (SCLC), which is Rb negative. Most NSCLC and SCLC resection specimens and cell lines overexpress cyclin D1 (indicating that cyclin D1 overexpression and Rb inactivation can coexist in SCLC). However, 9 of 9 Rb-positive NSCLC cell lines have absent or low p16, while an Rb-negative NSCLC line and 5 of 5 SCLC cell lines have high levels of p16. In primary resection specimens, p16 was undetectable in 18 of 27 NSCLC samples and abundant in 4 of 5 SCLC samples. Our data confirm the predicted reciprocity between Rb inactivation and p16 expression in a common human malignancy and define differential p16 expression as a fundamental distinction between NSCLC and SCLC.
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PMID:Reciprocal Rb inactivation and p16INK4 expression in primary lung cancers and cell lines. 783 18

p16INK4A, a specific inhibitor of cyclin-dependent kinase (cdk)4 and cdk6, is a candidate tumor suppressor in malignancies with wild-type retinoblastoma (Rb). Loss of p16INK4A frees these cdks from inhibition, permitting constitutive phosphorylation of Rb and inactivation of its growth suppressive properties. Consistent with this model, Rb-positive non-small cell lung cancers (NSCLCs) have little or no detectable p16INK4A protein, whereas Rb-negative lung cancers have abundant p16INK4A. However, only some NSCLCs have homozygous deletions or nonsense mutations in a remaining p16INK4A allele, suggesting that other mechanisms must account for absent or low levels of p16INK4A protein. Here, we analyzed 9 Rb-positive NSCLC cell lines for the controls governing p16INK4A activity. Four lines had homozygous deletions of p16INK4A (SK-LU-1, SK-MES-1, A-427, and SW900), and three had a point mutation in a single allele. First, in H520 cells, the previously reported deletion at codon 45 results in a frameshift that produces no detectable protein. Second, in Calu-3 cells, a His to Tyr substitution at codon 83 produced a variant with a shortened half-life that was unable to form complexes with cdk4 or cdk6. Third, in H661 cells, the previously reported point mutation in the second intron splice donor site resulted in a smaller p16INK4A protein. Although this variant formed complexes with cdk4 and cdk6, it had a profoundly reduced half-life, producing low steady-state levels of p16INK4A and abundant levels of free cdks. Finally, Calu-1 and Calu-6 cells transcribed no detectable mRNA encoding authentic p16INK4A. These cell lines displayed methylation of the CpG island surrounding the first exon of p16INK4A and expressed abundant levels of a nontranslated mRNA containing an alternative first exon (E1 beta), as did all other cell lines in which the p16INK4A locus was not deleted. These data indicate that Rb-positive NSCLC cells have evolved a variety of pathways to suppress p16INK4A expression. Reintroduction of p16INK4A into these cell lines by retroviral transfer resulted in a reduced growth rate, increased abundance of hypophosphorylated Rb, accumulation of cells in G1, and a less transformed morphology in Rb-positive, but not Rb-negative cells, suggesting that loss of p16INK4A is essential for maintenance of the transformed phenotype.
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PMID:Multiple mechanisms of p16INK4A inactivation in non-small cell lung cancer cell lines. 852 14

Deletion at 9p21 is frequent in many tumor types. A candidate tumor suppressor gene, p16INK4a, was mapped to this region and is frequently inactivated by several different mechanisms in many tumor types, including non-small cell lung cancer, but not in small cell lung cancer (SCLC). p16 functions as a cyclin/CDK inhibitor to prevent phosphorylation of pRB. It has been demonstrated that most SCLCs have lost pRB but retained p16, and the inactivation of pRB excludes the inactivation of p16 and vice versa. To determine the potential existence of other tumor suppressor genes on the short arm of chromosome 9 in SCLC, we tested 46 primary SCLCs by microsatellite analysis. We found that more than 89% of the tumors exhibited loss of heterozygosity (LOH) at 9p with three distinct minimal deleted areas. Among those areas, LOH at 9p21 was most frequent (86%), with a peak at a marker 150 kb telomeric to p16INK4a. LOH was also observed in more than 50% of the tumors at two other regions, 9p22 and 9p13. Our data strongly suggest the presence of at least three novel tumor suppressor loci on 9p in SCLC, and further investigations to clone candidate tumor suppressor genes are warranted.
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PMID:Identification of three distinct tumor suppressor loci on the short arm of chromosome 9 in small cell lung cancer. 901 64

A total of 10 primary malignant lymphomas of the brain were examined for deletion, mutation, and 5' CpG island methylation of the p16 gene, which is a candidate tumor suppressor gene with CDK-inhibitory function. In Southern blot analysis, p16 gene deletion was suggested in nine cases, homozygously (five cases) or hemizygously (four cases). In the remaining one case, p16 gene deletion was not suggested. Although single-strand conformation polymorphism and nucleotide analyses suggested no mutations of the p16 gene in these cases, methylation analyses revealed 5' CpG island methylation in three cases, of which two were those with presumed hemizygous deletion and one was that without deletion in Southern blot analysis. Thus, p16 gene abnormality was detected in all 10 of the brain lymphomas examined, and in 8 of them, actual p16 gene inactivation was suggested by their homozygous deletion (5 cases) or 5' CpG island methylation (3 cases). These findings suggest that p16 gene abnormality and inactivation are closely related to carcinogenesis in primary malignant lymphoma of the brain. The p15 gene, another candidate tumor suppressor gene located in the vicinity of the p16 gene, to which it shows structural and functional similarity, was also presumed to be deleted similarly in most cases. Its methylation was seen in one case, the case without the methylated p16 gene.
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PMID:Frequent deletion and 5' CpG island methylation of the p16 gene in primary malignant lymphoma of the brain. 951 10

CTCF is a multifunctional transcription factor encoded by a novel candidate tumor suppressor gene (Filippova, G. N., Lindblom, A., Meinke, L. J., Klenova, E. M., Neiman, P. E., Collins, S. J., Doggett, N. D., and Lobanenkov, V. V. (1998) Genes Chromosomes Cancer 22, 26-36). We characterized genomic organization of the chicken CTCF (chCTCF) gene, and studied the chCTCF promoter. Genomic locus of chCTCF contains a GC-rich untranslated exon separated from seven coding exons by a long intron. The 2-kilobase pair region upstream of the major transcription start site contains a CpG island marked by a "Not-knot" that includes sequence motifs characteristic of a TATA-less promoter of housekeeping genes. When fused upstream of a reporter chloramphenicol acetyltransferase gene, it acts as a strong transcriptional promoter in transient transfection experiments. The minimal 180-base pair chCTCF promoter region that is fully sufficient to confer high level transcriptional activity to the reporter contains high affinity binding element for the transcription factor YY1. This element is strictly conserved in chicken, mouse, and human CTCF genes. Mutations in the core nucleotides of the YY1 element reduce transcriptional activity of the minimal chCTCF promoter, indicating that the conserved YY1-binding sequence is critical for transcriptional regulation of vertebrate CTCF genes. We also noted in the chCTCF promoter several elements previously characterized in cell cycle-regulated genes, including the "cell cycle-dependent element" and "cell cycle gene homology region" motifs shown to be important for S/G2-specific up-regulation of cdc25C, cdc2, cyclin A, and Plk (polo-like kinase) gene promoters. Presence of the cell cycle-dependent element/cell cycle gene homology region element suggested that chCTCF expression may be cell cycle-regulated. We show that both levels of the endogenous chCTCF mRNA, and the activity of the stably transfected chCTCF promoter constructs, increase in S/G2 cells.
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PMID:Characterization of the chicken CTCF genomic locus, and initial study of the cell cycle-regulated promoter of the gene. 975 95

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

ik3-2 is a close relative to ik3-1/Cables, an associator with cdk3 and cdk5. ik3-1/Cables has been identified to be a candidate tumor suppressor for colon and head/neck cancers. In agreement, it has been pointed out that ik3-1/Cables is a regulator for both p53- and p73-induced apoptosis [J. Biol. Chem. 277 (2002) 2951] although ectopic expression of ik3-1/Cables does not induce apoptosis. Here we show that adenovirus-mediated overexpression of ik3-2 results in apoptosis of p53-intact U2OS cells. ik3-2 binds to p53 in vivo and ectopic coexpression of ik3-2 enhances apoptosis induced by adenovirus-mediated expression of p53. Furthermore, ectopic expression of ik3-2 results in apoptosis of primary p53/Mdm2- and p53/ARF-null mouse embryo fibroblasts, indicating that ik3-2-induced apoptosis is partially p53-independent. Both the highly conserved C-terminal cyclin box-homologous domain (ik3-2-C) and the N-terminal region consisting of 70 amino acids (ik3-2-N) are responsible for ik3-2-mediated enhancement of p53-induced apoptosis. In contrast, ik3-2-induced p53-independent apoptosis is mediated through ik3-2-N. We thus identified ik3-2 as a proapoptotic factor involved in both p53-mediated and p53-independent apoptotic pathways.
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PMID:ik3-2, a relative to ik3-1/Cables, is involved in both p53-mediated and p53-independent apoptotic pathways. 1463 68

hCLCA2 is frequently down-regulated in breast cancer and is a candidate tumor suppressor gene. We show here that the hCLCA2 gene is strongly induced by p53 in response to DNA damage. Adenoviral expression of p53 induces hCLCA2 in a variety of breast cell lines. Further, we find that p53 binds to consensus elements in the hCLCA2 promoter and mutation of these sites abolishes p53-responsiveness and induction by DNA damage. Adenoviral transduction of hCLCA2 into immortalized cells induces p53, CDK inhibitors p21 and p27, and cell cycle arrest by 24 hours, and caspase induction and apoptosis by 40 hours postinfection. Transduction of the malignant tumor cell line BT549 on the other hand does not induce p53, p21, or p27 but instead induces apoptosis directly and more rapidly. Knockout and knockdown studies indicate that growth inhibition and apoptosis are signaled via multiple pathways. Conversely, suppression of hCLCA2 by RNA interference enhances proliferation of MCF10A and reduces sensitivity to doxorubicin. Gene expression profiles indicate that hCLCA2 levels are strongly predictive of tumor cell sensitivity to doxorubicin and other chemotherapeutics. Because certain Cl(-) channels are proposed to promote apoptosis by reducing intracellular pH, we tested whether, and established that, hCLCA2 enhances Cl(-) current in breast cancer cells and reduces pH to approximately 6.7. These results reveal hCLCA2 as a novel p53-inducible growth inhibitor, explain how its down-regulation confers a survival advantage to tumor cells, and suggest both prognostic and therapeutic applications.
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PMID:hCLCA2 Is a p53-Inducible Inhibitor of Breast Cancer Cell Proliferation. 1965 13

Cables1 is a candidate tumor suppressor that negatively regulates cell growth by inhibiting cyclin-dependent kinases. Cables1 expression is lost frequently in human cancer but little is known about its regulation. Here, we report that Cables1 levels are controlled by a phosphorylation and 14-3-3-dependent mechanism. Mutagenic analyses identified two residues, T44 and T150, that are specifically critical for 14-3-3 binding and that serve as substrates for phosphorylation by the cell survival kinase Akt, which by binding directly to Cables1 recruits 14-3-3 to the complex. In cells, Cables1 overexpression induced apoptosis and inhibited cell growth in part by stabilizing p21 and decreasing Cdk2 kinase activity. Ectopic expression of activated Akt (AKT1) prevented Cables1-induced apoptosis. Clinically, levels of phosphorylated Cables1 and phosphorylated Akt correlated with each other in human lung cancer specimens, consistent with pathophysiologic significance. Together, our results illuminated a dynamic regulatory system through which activated Akt and 14-3-3 work directly together to neutralize a potent tumor suppressor function of Cables1.
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PMID:Cables1 complex couples survival signaling to the cell death machinery. 2536 94


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