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

We have recently reported that inactivation of the p16 gene by mutation and deletion is common in nasopharyngeal carcinoma (NPC). The present study demonstrates that hypermethylation of the 5' CpG island can serve as an alternative mechanism for inactivation of the p16 gene in this tumor. Using Southern blotting analysis and multiplex PCR, aberrant methylation of the 5' CpG island of the p16 gene was found in a NPC xenograft (xeno-666) and 6 (22%) of 27 primary tumors, but not in normal tissues of the nasopharynx. In the NPC xenograft (xeno-666) and its newly derived cell line (cell-666), both showing hypermethylation of the p16 gene, no p16 gene expression was found. After treatment with 5-aza-2'-deoxycytidine, reexpression of the p16 gene was detected in the cell line cell-666. These findings suggest that aberrant methylation of the 5' CpG island may participate in the transcriptional inactivation of the p16 gene in NPC. The present results further support that the p16 gene is the critical target on chromosome 9p21 for inactivation during the development of this disease.
 ...
PMID:Hypermethylation of the p16 gene in nasopharyngeal carcinoma. 866 2

Altered expression or function of the p16CDKN2 tumor suppressor gene on chromosome 9p21 occurs in a wide range of human tumors, and mutations in the gene have been shown to segregate with familial predisposition to malignant melanoma. We have used a variety of assays to examine the functional properties of tumor-associated alleles, including eight premature termination mutants, eight missense mutants, and three isoforms of p16 initiated at different amino-terminal methionine codons. The amino- and carboxy-terminal domains of the protein, outside the ankyrin-like repeats, appeared to be dispensable, but the majority of the premature termination mutations led to loss of function. Of the missense mutations tested, four displayed clear loss of function whereas two behaved like the wild type under all conditions tested. The remaining two mutations, a G-to-W mutation at position 101 (Gl01W) and V126D, both of which are associated with familial melanoma, were found to be temperature sensitive for binding to Cdk4 and Cdk6 in vitro, for inhibiting cyclin D1-Cdk4 in a reconstituted pRb-kinase assay, and for increasing the proportion of G1-phase cells following transfection. These findings clarify previous disparities and argue strongly that p16CDKN2 is a bona fide tumor suppressor associated with familial melanoma.
 ...
PMID:Temperature-sensitive mutants of p16CDKN2 associated with familial melanoma. 866 2

The p16 gene (MTS1 or CDK4I) encoding an inhibitor of cyclin-dependent kinase 4 (cdk4), has been reported to be deleted in various tumor cell lines, including lines derived from leukemic cells. The reported frequency of p16 gene loss is much higher in established cell lines than in primary tumor specimens. We investigated the status of the p16 gene in pediatric leukemias using 12 established cell lines of differing phenotypes and their corresponding primary leukemic cells. Six of 12 cell lines, including acute lymphoblastic leukemia (ALL) lines of T-cell (three of four), of precursor-B cell (two of four) and of mixed phenotype (one of four), showed homozygous deletion of the p16 gene using PCR and Southern blotting. Comparison of the cell lines with their corresponding primary leukemic cells clearly showed that in all 12 paired samples there were identical findings with respect to the presence or absence of the p16 gene, demonstrating that loss of the gene was a feature of the primary leukemic cells. This is the first study to show this correlation using a panel of paired samples, indicating that p16 gene deletions were not an artifact of in vitro cell culture. Furthermore, the survival of ALL patients with p16 gene deletions was significantly inferior to those without deletions, suggesting that this genetic alteration may be a clinical prognostic factor.
 ...
PMID:Deletions of the p16 gene in pediatric leukemia and corresponding cell lines. 866 50

Recent advances in molecular biology have revealed various genetic lesions in lung cancer. Mutations of the K-ras gene, amplification or overexpression of myc family genes, erbB2 gene, or bcl2 gene are frequent genetic changes of oncogenes in lung cancer. Inactivation of tumor suppressor genes such as Rb gene, p53 gene, or p16 gene are also seen rather frequently. Furthermore, loss of heterozygosity at certain chromosomal arms such as 3p, 5q, 18q and 22q suggesting inactivation of yet unidentified tumor suppressor genes, also occurs in a significant proportion of lung cancers. Most of these genetic lesions have been reported to be associated with a poor prognostic outcome of the patients. However, great controversy exists as to whether a certain genetic lesion is really a prognostic marker. For example, although about 20 studies have been published, the prognostic implications of the p53 gene for patients with lung cancer still remain unclear. Little is known about the mechanism through which a certain genetic change affects the patient's prognosis. To ultimately improve the prognosis of patients with this deadly disease, definitive studies on which subsequent clinical trials can rely are much awaited.
 ...
PMID:[Genetic abnormalities in lung cancer and their prognostic implications]. 868 34

The investigation of molecular evidence of gastric carcinoma will be contributable to the prevention, gene diagnosis and therapy of human gastric neoplasms. To determine the specific genetic change in human gastric cancer (HGC) and precancerous lesions, we analysized FISH, PCR/SSCP, IHC and DNA sequencing by using multiple probes to detect the gene abnormalities (mutation, deletion, amplification or overexpression of genes) of 67 fresh tumors, 63 endoscopic biopsies including 30 dysplasia (DYS) and 33 intestinal metaplasia (IM, and 4 tumor cell lines from HGC patients. Multiple genetic abnormalities including hypomethylation of H-ras gene, amplification and overexpression of met and erbB2, deletion of APC, mts1/p16, p53 and nm23 gene and point mutation of p53 gene were noted in HGC and precancerous lesion of human gastric mucosa. Among these changes, p53 gene was the highest frequence genetic alteration in 39/67 (54-58%) of gastric carcinoma. These results indicate that overexpression of met and H-ras occurs at early stage in progression of neoplasia, amplification of met, erbB2 and akt2 gene occurs at progressing stage of tumorigenesis, deletion of p53, APC, mts1/p16 and nm23 occurs at advanced stage in the progression of cancer. The abnormalities should be associated with malignant phenotypes: poor differentiation, vascular invasion, lymph nodes metastasis, and low survival time. We detected p53 gene mutation in both cancer and precancerous lesions of IM and DYS. These results suggest that p53 may be a susceptible gene and alteration of p53 gene plays an important role in the development of HGC.
 ...
PMID:[Multiple gene alterations involved in the processor of human gastric carcinogenesis]. 869 90

The tumor suppressor gene p16 (CDKN2/MTS-1/INK4A) can be inactivated by multiple genetic mechanisms. We analyzed 29 invasive primary head and neck squamous cell carcinomas (HNSCC) for p16 inactivation with immunohistochemistry utilizing a new monoclonal antibody (mAb), DCS-50. p16 staining of the primary lesions was correlated with genetic analysis including: (a) detailed microsatellite analysis of markers at the p16 locus to detect homozygous deletion; (b) sequence analysis of p16; and (c) Southern blot analysis to determine the methylation status of the 5' CpG island of p16. Twenty-four of 29 (83%) head and neck squamous cell carcinoma tumors displayed an absence of p16 nuclear staining using immunohistochemistry. Of these 24 tumors, we found that 16 (67%) harbored homozygous deletions, 5 (21%) were methylated, 1 displayed a rearrangement at the p16 locus, and 1 displayed a frameshift mutation in exon 1. These data suggest that: (a) inactivation of the p16 tumor suppressor gene is a frequent event in squamous cell carcinomas of the head and neck; (b) p16 is inactivated by several distinct and exclusive events including homozygous deletion, point mutation, and promoter methylation; and (c) immunohistochemical analysis for expression of the p16 gene product is an accurate and relatively simple method for evaluating p16 gene inactivation.
 ...
PMID:High frequency of p16 (CDKN2/MTS-1/INK4A) inactivation in head and neck squamous cell carcinoma. 870 96

In the cold winter of 1966 Aleksay Olovnikov, a theoretical biologist at the Academy of Sciences in Moscow, was waiting in the subway station where he was hit by the idea that the ends of linear chromosomes can't be replicated fully during each round of replication. In a theoretical paper (Olovnikov, 1971) he proposed that in somatic cells the ends of the chromosomes are not fully replicated during DNA synthesis, resulting in the shortening of linear DNA molecules with each cell division, and that this may be the cause of cell cycle arrest in senescent cells. Almost two decades after this proposal, Calvin Harley and co-workers found that telomeres, the physical ends of human chromosomes, shorten as a function of age in human cells in vitro and in vivo. The telomere hypothesis proposes that critically short telomeres may act as a mitotic clock to signal the cell cycle arrest at senescence (Harley, 1991). Here, we extend the telomere hypothesis and propose a model that incorporates recent advances in tumor suppressors and cell cycle control with several areas of cell aging. We propose that telomere shortening per se is not the direct signal for cell cycle arrest. It is the consequence of telomere loss, which may lead to generation of ds or ss DNA breaks. These breaks activate a p53 dependent or independent DNA-damage pathway that leads to the induction of a family of inhibitors of cyclin dependent kinases (including p21 and p16) and the eventual G1 block of senescence. In agreement with this hypothesis, we demonstrate that the level of p53 protein increases in near senescent cultures of MDFs. This increase may be responsible for induction of p21 (Noda, 1993) and IGF-Bp3 (Goldstein, 1991).
 ...
PMID:From telomere loss to p53 induction and activation of a DNA-damage pathway at senescence: the telomere loss/DNA damage model of cell aging. 870 99

The concept that lymphomagenesis is a multistep process is now widely accepted. Various factors are involved in the development and malignant progression of B-cell lymphoproliferative disorders. The most frequently recognized alterations in these disorders are chromosomal translocations which lead to the activation of proto-oncogenes (c-myc) or genes encoding for proteins involved in the control of the cell cycle (cyclin D1), differentiation (bcl-6) and apoptosis (bcl-2). In addition, genetic changes that inactivate tumor suppressor genes (p53, Rb, p16) have recently been identified. Infectious agents may also play a role in lymphomagenesis either by directly driving B-cell proliferation (EBV) or by inducing a chronic antigenic stimulation (EBV, HCV, HBV, helicobacter pylori). Finally, several data indicate that local cytokine networks and, in particular, autocrine (IL-6, IL-10) and/or paracrine (IL-2, IL-4, IL-6) loops probably play a contributory role in the development and evolution of B-cell lymphoproliferation. In the last few years, the advent of molecular biology techniques has allowed important advances in the definition of the events involved i the earlier phases of lymphoma development. This has been made possible, in particular, by the study of a series of oligoclonal or monoclonal lymphoproliferative disorders characterized by an indolent or "smoldering" clinical course, such as follicular lymphoma and the lymphoproliferation associated with autoimmune diseases, which are at high risk of evolution to a highly malignant lymphoma. In nearly all of these conditions, the clonal B-cells responsible for the early stages of the disease are probably not fully transformed and retain various degrees of responsiveness to a wide variety of microenvironmental stimuli (antigen or autoantigen stimulation, interactions with "reactive" T lymphocytes, local cytokine networks). These latter in turn may induce the regression of pathological lesions, maintain the disease in an active state or contribute to the evolution towards an overtly malignant lymphoma. These findings open new avenues for the design of unconventional strategies of intervention aimed at preventing the malignant evolution of pre-lymphomatous lesions and controlling the clinical course of certain low-grade B-cell lymphomas.
 ...
PMID:Cellular and molecular bases of B-cell clonal expansions. 872 94

A melanoma predisposition gene has been identified. This gene, CDKN2, maps to chromosome 9p21-p22 and encodes p16, an inhibitor of cyclin-dependent kinases 4 and 6. CDKN2 has been found to be inactivated by homozygous deletion or intragenic mutation at high frequency in a diverse range of tumors and tumor cell lines, including those derived from melanomas. Now a number of CDKN2 mutations have been found in the germline of affected members of melanoma kindreds, and biochemical analysis of the mutant proteins has confirmed that they are functionally compromised. Unexpectedly, no germline CDKN2 mutations have been found in about half of the melanoma families that appear to be linked to 9p. Regulatory mutations outside of the coding region are being sought in these families. A number of other kindreds do not appear linked to 9p, hence the search continues for a second melanoma susceptibility gene.
 ...
PMID:The current situation with regard to human melanoma and genetic inferences. 872 6

Because allelotype analysis of many tumors has been important in the identification of new tumor suppressor genes, here we have analyzed hepatocellular carcinomas (HCCs) derived from F1 hybrid mice between C3H and MSM in detail. The analysis showed no allelic loss in primary HCCs, while the loss was detected in tumor cell lines established from HCCs. Recently, a candidate tumor suppressor gene termed p16/CDKN2, which was located near the interferon gene cluster on human chromosome 9p21, was identified by virtue of its frequent homozygous deletion in cell lines derived from many different tumor types. Since frequent allelic imbalances in the D4MIT9 locus and loss of heterozygosity in the alpha-interferon gene which was located near the mouse homolog of p16/CDKN2 (mouse p16) gene were detected in tumor cell lines, we investigated homozygous deletion of the mouse p16 gene by the comparative multiplex PCR method. The analysis revealed frequent homozygous deletion of the gene in thirteen of the tumor cell lines (13/25, 52%), but not in primary HCCs (0/25, 0%). These data indicate that gene deletions including the mouse p16 gene on chromosome 4 in tumor cell lines occur during the culture and that allelic imbalances are uncommon in mouse primary HCCs. Our results suggest that mouse p16 plays an important role in mouse hepatocarcinogenesis in vivo in progression or immortalization in vitro.
 ...
PMID:Allelotype analysis in mouse hepatocellular carcinomas; frequent homozygous deletion of mouse homolog of p16/CDKN2 gene on chromosome 4 in culture. 874 75


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