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)

Previous experiments have demonstrated that the regulation of E2F-1 transcription factor activity is critical for the maintenance of normal cell proliferation control. Regulation of E2F-1 is accomplished through at least two mechanisms: posttranslational regulation by binding proteins such as Rb and transcriptional regulation of the E2F-1 gene. The E2F-1 gene promoter has recently been isolated to examine this latter aspect of E2F-1 regulation. Preliminary studies demonstrate that the E2F-1 promoter is under E2F-dependent negative control during the cell growth response, being transcriptionally repressed through E2F sites in G0 and early G1. We now demonstrate that the presence of an E2F DNA-binding complex containing the Rb-related p130 protein (Rb2) correlates with E2F-1 gene repression and that overexpression of p130 inhibits transcription from the E2F-1 promoter. Moreover, D-type cyclin-dependent kinase activity specifically activates the E2F-1 promoter by relieving E2F-mediated repression but is inhibited by coexpression of the cdk4 and cdk6 inhibitor p16 (CDKN2, MTS1, INK4). Taken together, these findings suggest that E2F-1 gene expression is controlled during cell cycle progression by a regulatory network involving at least one oncogene (cyclin D1) and several potential tumor suppressor genes.
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PMID:Regulation of E2F-1 gene expression by p130 (Rb2) and D-type cyclin kinase activity. 747 95

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

In this study the expression of p16INK4, retinoblastoma protein (pRb), and cdk4 proteins have been examined in 18 malignant glioma cell lines and in 45 malignant glial tumors. Loss of p16INK4 expression associated with p16INK4 gene homozygous deletion was evident in 12 cell lines and in 10 primary tumors. Lack of p16INK4 expression was also evident in five tumors for which there was no evidence of p16INK4 gene homozygous deletion. Two of the cell lines and six of the primary tumors in which p16INK4 was present were determined to overexpress cdk4 in association with CDK4 gene amplification. Absence of pRb was determined in two of the cell lines and in ten of the tumors. In total, 16 of 18 cell lines and 25 of 45 tumors showed either a lack of p16INK4 or pRb or amplification-associated overexpression of cdk4. Two additional tumors showed an absence of pRb and p16INK4, and one tumor showed a lack of pRb combined with amplification-associated overexpression of cdk4. These results suggest a common growth-regulatory mechanism that is disrupted in gliomas by either suppressing the expression of p16INK4 or pRb or by increasing the expression of cdk4.
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PMID:Lack of p16INK4 or retinoblastoma protein (pRb), or amplification-associated overexpression of cdk4 is observed in distinct subsets of malignant glial tumors and cell lines. 758 16

Human cervical cancers frequently contain retinoblastoma protein (Rb) that is inactivated by binding with human papilloma virus (HPV) E7 protein or through mutation. The CDKN2 gene encodes p16INK4 which inhibits cdk4-cyclin D phosphorylation of Rb, preventing the G1-S transition. To determine whether abnormalities of CDKN2 occur in cervical-cancer cells, II cervical cell lines, including 8 HPV-positive cell lines, 2 HPV-negative cell lines containing mutant Rb, and one tumorigenic cell line derived from normal cervical cells following transfection with HPV-16 and v-H-ras (CX16-2HR), were analyzed. No cell line had a homozygous deletion of exon 1 or 2 of CDKN2, and only one cell line, CX16-2HR, had an altered DNA sequence, which represents a common polymorphism at codon 148. To exclude the possibility of other subtle inactivating mutations, immunoblot analysis of protein lysates was performed using a polyclonal anti-p16INK4 rabbit anti-serum. Abundant levels of normal-sized p16INK4 were observed in all cell samples. Thus, no alterations of CDKN2 were detected in these cervical cell lines. These results confirm that mutational inactivation of p16INK4 is a rare event in tumor samples with compromised Rb activity.
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PMID:CDKN2 in HPV-positive and HPV-negative cervical-carcinoma cell lines. 759 Dec 9

The gene encoding the cell cycle inhibitor p16INK4A (also known as p16, MTS1, CDKN2 and INK4) has been mapped to human chromosome band 9p21, a region that also contains a putative melanoma susceptibility gene. Although germline mutations in the coding region of the p16INK4A gene have been detected in some families with inherited melanoma, many other families show no evidence of such mutations and hence the role of p16INK4A in the development of this tumor is still unclear. In this report, we describe a family with inherited melanoma in which a novel mutation in exon 2 of the p16INK4A gene segregates with the disease. The mutant gene encodes a protein with an in-frame deletion of two amino acids (Asp96 and Leu97). We show that the mutant protein is functionally abnormal: it is unable to bind cdk4 in vitro and does not inhibit colony formation in tertiary passage rat embryo fibroblasts. Moreover, in a metastatic lesion from one patient the wild type p16INK4A allele was deleted and the mutant allele retained. We conclude that family members carrying this germline mutation in the p16INK4A gene are predisposed to melanoma. By extension, these findings implicate the p16INK4A gene in the development of some cases of familial melanoma.
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PMID:Germline p16INK4A mutation and protein dysfunction in a family with inherited melanoma. 762 55

The cyclin-dependent kinase 4 (cdk4) inhibitor (p16INK4/MTS1/CDKN2) gene has been recently identified as a putative tumor suppressor gene because of the high frequency of homozygous deletion observed in numerous human tumor cell lines, including leukemias. However, results obtained from uncultured tumor samples have led to discussion of the relevance of these findings. Using reverse transcriptase polymerase chain reaction (RT-PCR) and Southern blot analysis, we have investigated p16INK4A gene at both RNA and genomic levels in various types of leukemias: acute myeloid leukemia (AML) (n = 23); acute lymphocytic leukemia (ALL) (n = 22) and B cell chronic lymphoproliferative disorders (CLPD) (n = 33). p16INK4A mRNA expression was not found in only 1/20 AML and 2/23 CLPD samples. Conversely, p16INK4A mRNA was not detected in 5/17 ALL cases, and intensity of PCR products were barely detectable in seven additional cases, possibly related to the contamination by normal cells in some cases. By Southern blotting, a homozygous deletion of p16INK4A gene was found in 6/17 ALL cases (35%) among which 4/6 were negative or weakly positive by RT-PCR assay. None of the five AML and 20 CLL samples studied had p16INK4A deletion. Sequence analysis of p16INK4A exon 2 did not show point mutation in two of these cases lacking mRNA expression. Our data provide further evidence that among hematological malignancies, ALL are the most likely to be associated with p16INK4A inactivation, mainly by homozygous gene deletion. Since most hematological malignancies-except ALL-are infrequently associated with p16INK4A and retinoblastoma (Rb) gene alteration it seems worthwhile to explore cdk4 and cdk6 expression to determine whether or not the disruption of the p16INK4A/Rb/cdk4/cdk6 regulatory loop might play a role in their pathogenesis.
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PMID:Alterations of cyclin-dependent kinase 4 inhibitor (p16INK4A/MTS1) gene structure and expression in acute lymphoblastic leukemias. 763 Jan 99

Homozygous deletions of the putative tumour-suppressor gene CDKN2, which encodes an inhibitor of cdk4, have been detected in a high percentage of cancer cell lines of various histological types. In the present study, 109 human sarcomas were examined for homozygous deletions and for mRNA expression levels of the CDKN2 gene. Altogether, deletions were found in only eight (7%) of the cases, but, interestingly, in two (of eight) malignant Schwannomas and in two (of five) rhabdomyosarcomas. In comparison, such deletions were seen in only one (of 21) osteosarcomas and in none of 20 MFHs and 21 liposarcomas. Notably, highly elevated CDKN2 mRNA levels were found in 33% of the sarcomas, whereas no detectable transcript was present in 12 normal tissues. Amplifications of CDK4 and CCND1 (cyclin D1) were observed in 11% and 4% of the sarcomas respectively, but never in tumours with CDKN2 deletions. The level of CDK4 mRNA expression was increased in nine tumours in addition to the 12 samples with CDK4 amplification. Increased levels of the cyclin D1 transcript was found in 37 cases, four with and 33 without amplification. The data indicate that aberrations of these functionally related genes, or in regulation of the expression of the kinase, the activator or the inhibitor, may participate in sarcoma development. Furthermore, the data suggest that homozygous CDKN2 deletions may be of dissimilar significance in different sarcoma subtypes.
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PMID:Homozygous deletion frequency and expression levels of the CDKN2 gene in human sarcomas--relationship to amplification and mRNA levels of CDK4 and CCND1. 764 Feb 24

Cell division is controlled by a series of positive and negative regulators which act at sequential points throughout the cell cycle. Disturbance of these checks could contribute to cancer by allowing excessive cell proliferation. The point in G1 at which cells irrevocably commit to DNA synthesis is controlled by protein complexes consisting of cyclin-dependent kinases (CDK4 or CDK6) and cyclins (D1, D2 or D3). These complexes are inhibited by low molecular weight proteins, such as p16INK4 (refs 1,2), p15INK4B (ref. 3) and p18 (ref. 4). Deletion or mutation of these CDK-inhibitors could lead to unchecked cell growth, suggesting that members of the p16INK4 family may be tumour suppressor genes. The recent detection of p16INK4 (MTS1) mutations in familial melanoma kindreds, many human tumour cell lines, and primary tumours is consistent with this idea. Previously, we described eight germline p16INK4 substitutions in 18 familial melanoma kindreds. Genetic analyses suggested that five mutations predisposed carriers to melanoma, whereas two missense mutations had no phenotypic effect. We now describe biochemical analyses of the missense germline mutations and a single somatic mutation detected in these families. Only the melanoma-predisposing mutants were impaired in their ability to inhibit the catalytic activity of the cyclin D1/CDK4 and cyclin D1/CDK6 complexes in vitro. Our data provide a biochemical rationale for the hypothesis that carriers of certain p16INK4 mutations are at increased risk of developing melanoma.
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PMID:Mutations associated with familial melanoma impair p16INK4 function. 764 80

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.
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PMID:Cloning and characterization of murine p16INK4a and p15INK4b genes. 765 26

The CDKN2 gene located on chromosome 9p21 encodes the cyclin-dependent kinase-4 inhibitor p16. This gene is a putative tumor-suppressor gene because of its frequent alterations in many kinds of tumor cell lines. We analyzed the CDKN2 gene to evaluate its alterations in 52 primary specimens of non-Hodgkin's lymphoma (NHL) or chronic lymphocytic leukemia (CLL) of B-cell origin by Southern blot analysis, polymerase chain reaction-mediated single-strand conformation polymorphism (PCR-SSCP) analysis, and direct sequencing. By Southern blot analysis, we showed homozygous deletion of the CDKN2 gene in 3 of 42 patients with B-NHL (7.1%). After screening by PCR-SSCP analysis, direct sequencing identified one missense mutation at codon 72 (nucleotide 233) and two frameshifts due to a 35-bp deletion arising at codon 49 (nucleotides 163 to 175) in patients with B-NHL (3 of 42, 7.1%). In the patient carrying the missense mutation, hemizygous deletion of the CDKN2 gene was also suspected. In this study, we detected alterations in CDKN2 in 6 of 42 patients (14.3%) with B-NHL and in none of 10 patients with B-CLL. Our results suggest that the CDKN2 alterations contribute in tumorigenesis in some patients with B-NHL.
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PMID:Mutational analysis of the CDKN2 (MTS1/p16ink4A) gene in primary B-cell lymphomas. 767 Jan 11


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