Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The p16Ink4/CDKN2, D-type cyclins, their partners Cdk4/Cdk6, and pRb constitute a G1 regulatory pathway commonly targeted in tumorigenesis. Genetic, immunochemical, and functional cell cycle analyses showed abnormalities of this pathway in each of 22 human melanoma cell lines examined. Normal melanocytes and all melanoma lines expressed Cdk4, Cdk6, and cyclins D1 and D3. The tumor suppressors p16Ink4/CDKN2 and pRb were lost in 17 and 4 cases, respectively, due to various genetic mechanisms, including transcriptional block of p16 and nonsense mutations of RB1. Ectopic expression of p16 prevented S-phase entry of Rb+/p16- but not Rb-deficient melanoma lines. The SK29-MEL-1 cell line harboring an R24C mutation in Cdk4 expressed wild-type pRb and overabundant p16, the latter preventing endogenous Cdk6 but not Cdk4 from associating with cyclin D1. Microinjection of cyclin D1-neutralizing antibody arrested the SK29-MEL-1 cells in G1, whereas pl6 did not, indicating that the cyclin D1/Cdk4-R24C complex is required for G1 progression, and the resistance of the complex to p16 in vivo. These data strongly support the candidacy of Cdk4 as a novel proto-oncogene, provide further evidence for the p16-cyclin D/Cdk-pRb pathway as a functional unit, and suggest that deregulation of this checkpoint may represent a common step in the multistep progression of sporadic malignant melanomas.
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PMID:The p16-cyclin D/Cdk4-pRb pathway as a functional unit frequently altered in melanoma pathogenesis. 896 4

p16INK4 protein (p16) and retinoblastoma protein (pRB), like p53 protein, are important tumor suppressors that regulate the cell cycle. We immunohistochemically examined fresh-frozen specimens of 114 resected non-small cell lung cancers (NSCLCs) for loss of p16 and pRB expression, together with aberrant accumulation of p53 protein and the proliferative activity determined by the Ki-67 index. Three pRB-positive tumors were uninterpretable for p16 status. Of the remaining 111 tumors, 30 (27%) lacked p16 expression, and 10 (9%) lost pRB expression. No tumors showed coincident loss of both proteins, supporting the hypothesis that they function in a single pathway. Of 25 tumors, including 4 p16-negative tumors, examined by Southern blot analysis, only 2 p16-negative tumors were considered to have reduced gene dosage consistent with possible homozygous deletion of the CDKN2 gene encoding p16, suggesting that immunohistochemistry is a sensitive and suitable method to screen for p16 alteration. Loss of p16 expression did not correlate with any clinical factors or p53 status, whereas loss of pRB expression correlated with heavy smoking (P = 0.03 by Fisher's exact test and P = 0.01 by the multivariate logistic regression analysis). Proliferative activity was considerably higher in p53-positive tumors than in p53-negative tumors (P < 0.001). Loss of p16 or pRB expression was associated with a further increase in proliferative activity in the p53-positive tumors (P = 0.009) but not with proliferative activity in the p53-negative tumors. These results suggest that alteration of the p16/pRB pathway is relatively frequently involved in the development and progression of NSCLCs and that its effect on the proliferative activity is potentially synergistic with altered p53 protein.
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PMID:Altered p16INK4 and retinoblastoma protein status in non-small cell lung cancer: potential synergistic effect with altered p53 protein on proliferative activity. 897 Nov 52

We have PCR-amplified and sequenced the immediate (841 bp) 5'-flanking region of murine p16INK4a (MTS1, CDKN2) tumor suppressor gene. Comparing to recently published 5'-flanking region of the human alpha form of p16INK4a, homologies were found in several regions of murine p16INK4a-alpha putative promoter sequence.
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PMID:The 5'-flanking region of the E1 alpha form of the murine p16INK4a (MTS1) gene. 897 69

Cytogenetic and molecular studies have implied the presence of tumor suppressor genes (TSGs) on chromosome 9p that are critical in the development of lung and other cancers. The p16/CDKN2 gene, a cyclin dependent kinase inhibitor, is a well-defined TSG on 9p21. Although the frequency of mutations in the p16/CDKN2 gene has been detected in approximately 30% of non-small cell lung cancer, loss of heterozygosity on 9p has been observed in greater than 70% of non-small cell lung cancers. These and other deletion mapping studies have suggested the existence of additional TSGs on 9p. This study examined chromosome 9p for TSG loci by analyzing 23 squamous cell carcinomas of the lung with 21 microsatellite markers. Loss of heterozygosity was detected in all of the tumors, and homozygous deletions of the p16/ CDKN2 locus were observed in 6 of the 23 tumors (26%). In addition, a novel region of homozygous deletion was detected in six tumors (26%) at D9S126, approximately 2.5 cM proximal to p16/CDKN2. A single tumor contained a homozygous deletion at both the p16/CDKN2 locus and the D9S126 locus. The possibility of homozygous loss was confirmed by multiplex PCR using both the D9S126 marker and a chromosome 9p control marker. Fluorescence in situ hybridization analysis with P1 and cosmid probes containing D9S126 also confirmed these data. The minimum region of homozygous deletion was determined by testing markers immediately proximal and distal to the D9S126 region. The data identify a homozygous loss on the short arm of chromosome 9 suggesting the presence of a novel TSG locus, proximal to p16/CDKN2 and located between D9S265 and D9S259.
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PMID:Identification of a novel region of homozygous deletion on chromosome 9p in squamous cell carcinoma of the lung: the location of a putative tumor suppressor gene. 898 29

Deregulation of the cell cycle by abnormal expression of one or several cell cycle regulatory proteins is a common finding in malignant tumors and might be a prerequisite for cancer development. Telomerase activity is an immortalization marker that is found in most cancers and for which an association with an active cell cycle has been implicated. In the tissue of 106 human breast carcinomas, we analyzed the relationship between telomerase activity levels and defects in the cell cycle machinery with a focus on the retinoblastoma protein (pRB) pathway(s). The fraction of telomerase-positive tumors was 85%, and large differences in telomerase activity were found. Overexpression of cyclin D1 and/or cyclin E, in combination with a normal pRB, was a typical feature of tumors with high telomerase activity levels. Down-regulation of p16INK4 was not related per se to telomerase activity, but tumors with low p16INK4 in combination with cyclin D1 or E overexpression demonstrated high activity. Tumor cell proliferation, determined by Ki-67 expression, correlated significantly to telomerase activity levels. There was, however, not a strict association between proliferation rate and telomerase activity, because tumors with inactivated pRB had the highest Ki-67 fractions but intermediate telomerase activity. Also, cyclin D1 overexpression was associated with high telomerase levels without an increase in tumor cell proliferation. The present study indicates that telomerase activation occurs preferentially in breast cancers with certain cell cycle regulatory defects and that telomerase activity levels may depend on the specific defect(s).
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PMID:Telomerase activity is associated with cell cycle deregulation in human breast cancer. 901 89

The INK4a gene, one of the most frequently disrupted tumor suppressor loci in human cancer, encodes two unrelated proteins, p16INK4a and p19ARF, each of which is capable of inducing cell cycle arrest. Splicing of alternative first exons (1 alpha vs. 1 beta) to a common second exon within INK4a generates mRNAs in which exon 2 sequences are translated in two different reading frames. One of the products, the cyclin D-dependent kinase inhibitor p16INK4a, is functionally inactivated by mutations or deletions in a wide variety of cancers. However, because many such mutations reside in exon 2, they also affect the alternative reading frame (ARF) protein. To determine whether such mutations disrupt p19ARF function, we introduced naturally occurring missense mutations into mouse INK4a exon 2 sequences and tested mutant p16INK4a and p19ARF proteins for their ability to inhibit cell cycle progression. Six p19ARF point mutants remained fully active in mediating cell cycle arrest in NIH 3T3 fibroblasts, whereas two of the corresponding mutations within p16INK4a resulted in complete loss of activity. Analysis of p19ARF deletion mutants indicated that the unique aminoterminal domain encoded by exon 1 beta was both necessary and sufficient for inducing G1 arrest. Therefore, cancer-associated mutations within exon 2 of the INK4a gene specifically target p16INK4a, and not p19ARF, for inactivation.
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PMID:Cancer-associated mutations at the INK4a locus cancel cell cycle arrest by p16INK4a but not by the alternative reading frame protein p19ARF. 901 42

p19INK4d is a 165 amino acid protein that belongs to the INK4 family of CDK4 and CDK6 inhibitors. Assignments of 1H, 15N and 13C resonances have enabled the determination of the secondary structure of the protein which is largely alpha-helical (residues 14-18, 21-29, 54-62, 77-83, 87-95, 110-116, 120-128, 142-148 and 152-160). The protein comprises five 32-amino acid ankyrin-like repeats; each ankyrin repeat contains a helix-beta-turn-helix core. The exception is the second ankyrin repeat, which lacks the first helix. All beta-turns have a central glycine residue flanked by two residues in beta-conformations. There is also a high conservation of Ala at position 8 in the first helix and Leu-Leu(Val) at positions 17-18 of the second helix in all ankyrin repeats of p19. The location of the helix-turn-helix segments found in p19 should be general for all other members of the INK4 family, including, for example, a homologous tumor suppressor p16INK4a. 1H-15N heteronuclear steady-state NOE measurements on p19 indicate that most of the backbone of p19INK4d exists in a well defined structure of limited conformational flexibility on the nano- to picosecond time scale.
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PMID:NMR structural characterization of the CDK inhibitor p19INK4d. 901 72

Neoplastic diseases are proliferative disorders characterized by uncoordinated cell growth. Cellular proliferation follows an orderly progression through the cell cycle, which is governed by different cyclins and cyclin dependent kinases (CDKs). Recently, CDK-inhibitors, which are a new class of small proteins involved in the negative regulation of the cell cycle, have been identified by virtue of their ability to interact physically with cyclin/CDK-complexes. As the genes encoding the CDK4- and CDK6-inhibitors (CDK4/6-inhibitors) p16INK4A/CDKN2/MTS1 and p15INK4B/MTS2 have been found to be altered in many cancer cell lines and primary neoplastic tissues, CDK-inhibitors in general and CDK4/6-inhibitors in particular are now a se: of candidate tumor suppressors. The p15 and p16 genes map to a region frequently deleted in lymphoid neoplasms. Therefore, considerable efforts have been made to determine the role of CDK4/6-inhibitors in hematologic malignancies: This article will review alterations of components of the cell-cycle machinery in brief and summarize the role of the CDK4/6-inhibitors p16INK4A, p15INK4B, p18INK4C and p19INK4D in leukemias and lymphomas.
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PMID:Role of the cyclin-dependent kinase 4 and 6 inhibitor gene family p15, p16, p18 and p19 in leukemia and lymphoma. 903 Oct 81

The recently discovered p15INK4B and p16INK4 genes encoding cell cycle regulating proteins, map to a region on chromosome 9p21 that is commonly deleted in a variety of malignant diseases. The p16INK4 gene has now been shown to be a tumor suppressor gene. It is frequently inactivated in cancer and is possibly the second most often mutated gene in human malignant disease after p53. The role of the p15INK4B and p16INK4 genes in hematologic malignancies has been the subject of intense investigation since their discovery. In this review we address the function and possible role in tumorigenesis of the p15INK4B and p16INK4 genes and discuss their significance as prognostic markers in hematologic malignancies.
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PMID:Inactivation of the p15INK4B and p16INK4 genes in hematologic malignancies. 903 Nov 4

The p16/CDKN2(MTS1) gene encoding for the p16 inhibitor of cyclin D/CDK4 complexes is frequently mutated and deleted in a large fraction of melanoma cell lines, and p16 germline mutations have also been observed in familial melanomas. Moreover, a CDK4 gene mutation, responsible for a functional resistance of CDK4 kinase to p16 inhibitory activity, has been described to occur in some cases of familial melanoma. These data strongly support the idea that deregulation of the CDK4/cyclin D pathway, via CDKN2 or CDK4 mutations, is of biological significance in the development of melanoma. To shed light on the role of these alterations in the development and progression of sporadic melanoma, 12 primary melanomas and 9 corresponding metastases were analyzed for CDKN2 and CDK4 gene mutations. Of the 12 primary melanomas analyzed, 4 showed the presence of mutational inactivation of the p 16 protein and 2 carried silent mutations. No metastases showed the presence of CDKN2 mutations, indicating that mutations of this cyclin-dependent kinase inhibitor is not common in the progression of sporadic melanoma. On the other hand, the absence, in the metastases, of the CDKN2 mutation detected in the corresponding primary tumors suggests that 9p21 homozygous deletion may play a major role in the metastatic spreading of this type of tumor. None of the cases analyzed showed the presence of an Arg24Cys mutation, which functionally protects CDK4 from p16 inhibition. This indicates that CDK4 mutation plays a minor role in the development and progression of sporadic melanoma.
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PMID:p16/CDKN2 and CDK4 gene mutations in sporadic melanoma development and progression. 903 65


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