Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0677930 (primary tumor)
 20,210 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The CDKN2 tumor suppressor gene encodes an inhibitor of type D cyclin dependent kinases. CDKN2 is homozygously deleted in approximately 25% of nonsmall cell lung cancer (NSCLC) cell lines and these deletions are associated with advanced stage cancer. Conflicting reports of the frequency of CDKN2 alterations in NSCLC tumors prompted us to examine the relationship of these alterations and those of the related gene, MTS2, with patient stage and site of cancer. One hundred twenty-five NSCLC samples (71 cell lines and 54 tumors) were examined by PCR-SSCP. Twenty of 71 (28%) tumor cell lines had homozygous deletions, and six (8%) had point mutations compared to 4 (7%) with point mutations among 54 tumor samples. All mutations were observed in tumors or cell lines from patients with stage III or IV disease. Two patients with no mutations in their primary tumor had a CDKN2 point mutation detected in a metastatic tumor. Point mutations were G:C to T:A transversion on the coding strand in five of 10 and resulted in nonsense mutations in seven of 10. Undetectable CDKN2 mRNA, in the absence of detectable genetic alteration, was noted in a similar fraction of cell lines derived from patients with stage I or II disease [two of seven (29%)] and stage III or IV disease [15 of 49 (31%)]. Homozygous deletion of MTS2 was found in 17 of 20 cell lines with CDKN2 deletions; no point mutations of MTS2 were identified by SSCP in the 125 samples. Thus, CDKN2 is a frequent target of genetic alterations at 9p21 in NSCLC. Both deletions and point mutations of CDKN2 are closely associated with tumor dissemination.
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PMID:Mechanism of inactivation of CDKN2 and MTS2 in non-small cell lung cancer and association with advanced stage. 747 13

Normal, nontumorous cells express cyclin proteins in an orderly, scheduled fashion, at a given phase of the cell cycle. Thus, cyclin B1 is synthesized during G2 and abruptly degraded during mitosis. The onset of cyclin E synthesis takes place in mid-G1, its maximal expression is at the time of cell entrance to S, and its degradation occurs during cell progression through S phase. In the present study, multiparameter flow cytometry was used to correlate expression of cyclin B1 or cyclin E with cell cycle position (estimated by cellular DNA content) in normal human proliferating lymphocytes as well as in T-cell MOLT-4 leukemia; promyelocytic HL-60 leukemia; histiocytic U937 lymphoma; MCF-7, T-47D, and Hs 587T breast carcinoma; Colo 320DM colon carcinoma; and the T-24 transitional cell carcinoma cell line. The scheduled expression of both cyclins, namely of cyclin B1 restricted to G2 + M cells and of cyclin E restricted to late G1 and early S cells, was observed only in normal lymphocytes and MOLT-4 cells. The cells of HL-60, U937, T-47D, and Hs 587T lines expressed both cyclins in an unscheduled ("ectopic") fashion, i.e., unrelated to cell cycle position. Colo 320DM cells showed unscheduled expression of cyclin E (i.e., during G2) but expression of cyclin B1 in this line was generally restricted to G2 + M cells. There were relatively few (10-12%) cells in MCF-7 and T-24 cell lines that expressed cyclin B1 or E in an unscheduled manner. It may be expected that the unscheduled expression of cyclins in tumor cells may lead to a loss of the regulatory mechanisms of cell cycle progression and that such feature of the tumor may be of prognostic value. There is a need, therefore, to conduct similar studies in primary tumor cells.
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PMID:Unscheduled expression of cyclin B1 and cyclin E in several leukemic and solid tumor cell lines. 804 72

Recent research has yielded a dramatic increase in the number of connections between oncogenesis and the proteins which regulate the cell cycle. Three classes of protein which inhibit the activity of cyclin-dependent kinases (CDKs) have emerged as potential targets for oncogenic inactivation. p16 and related proteins inhibit the cyclin/CDK complexes which regulate the transition from G1 to S phase; numerous studies have revealed that p16 is mutated in most tumor cell lines and in some types of primary tumor. p21/WAF1/Cip 1 and the related p27Kip protein inhibit a broader range of cyclin/CDK complexes than p16. Although the absence of p21/WAF1/Cip1 from cyclin/CDK complexes is correlated with cellular transformation, no mutations in this gene have been found in tumors or tumor-derived cell lines. A third class of genes which are potential targets for oncogenic inactivation are the kinases and phosphatases which regulate the activity of cyclin/CDK complexes by phosphorylation and dephosphorylation of the CDK proteins. Disruption of any of these genes would result in loss of normal regulation of cell growth.
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PMID:Inhibitors of cyclin-dependent kinase and cancer. 858 12

The product of the p16/CDKN2 locus, p16ink4, negatively regulates the cell cycle through binding and inactivation of cyclin-dependent kinases (CDKs) 4 and 6. This locus is frequently targeted for deletion in cell lines and primary tumor tissues. In gliomas, although up to 50% do not have detectable expression of p16/CDKN2 protein or mRNA, often the gene is wild type in sequence. Here, we tested the hypothesis that transcriptional repression of p16/CDKN2 in gliomas may be mediated by aberrant methylation of the CpG island, which is in the 5' region of the locus. Partial rather than complete p16/CDKN2 methylation was detected in 24% (10 of 42) of the gliomas, regardless of tumor grade, but was not observed in normal brain (0 of 10). We tested whether this partial methylation could inhibit expression in a human tumor cell line in which suppressed p16/CDKN2 expression was associated with both methylation and tightly compacted chromatin around the p16/CDKN2 promoter. Exposure of these cells to 5-aza-2-deoxycytidine resulted in a dramatic increase in promoter accessibility and induction of p16/CDKN2 expression, indicating that chromatin structure, CpG island methylation, and p16/CDKN2 expression are intimately associated. Taken together, these data suggest that methylation occurs in only a subset of cells within gliomas and that the methylation-associated inactivation of p16/CDKN2 expression observed in many common human cancers may mechanistically result from structural changes in the chromatin containing the p16/CDKN2 locus.
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PMID:Silencing of p16/CDKN2 expression in human gliomas by methylation and chromatin condensation. 862 19

This case report describes a dog with spontaneous melanoma of the orofacial region which was treated by a synthetic inhibitor of cyclin-dependent kinases, i.e. olomoucine (OC). The drug was applied i.v. in a single dose of 8 mg/kg/day for 7 days in succession. Repeated bioptic examinations of metastatic cervical lymph nodes showed rapid induction of apoptosis in tumor cells as early as on the third day of treatment. Standard clinical and laboratory examinations did not reveal side effects of the therapy. There were no detectable manifestations of myelosuppression, hepatotoxicity, nephrotoxicity or neurotoxicity. However, transient anemia developed following bleeding from a devitalized tumor mass. For this reason, the dog underwent surgery to minimize tumor load as well as to eliminate the source of bleeding. Two kilograms of primary tumor were extirpated in the course of surgery, including cervical node metastases. Unfortunately, the dog died soon after surgery due to respiratory depression. Histological examinations of the tumor tissue showed marked apoptosis of melanoma cells in both the primary tumor and metastases. The induction of programmed cell death of cancer cells by OC resulted in rapid eradication of at least 68% of the tumor cells. The remaining melanoma cells retained at least equally well in vitro sensitivity to OC as to drugs currently used in clinical practice.
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PMID:Induction of apoptosis and regression of spontaneous dog melanoma following in vivo application of synthetic cyclin-dependent kinase inhibitor olomoucine. 943 44

In vitro and animal studies, the effect of loss of p53 function on radiosensitivity is controversial. p21Waf1/Cip1 is a potent inhibitor of cyclin-dependent kinases and p21 gene polymorphisms are associated with some human cancers. We sought to determine whether p53 mutations or p21 polymorphisms affect response to radiotherapy in patients with recurrent non-small cell lung carcinoma (NSCLC). Thirty-four patients with NSCLC who underwent radiotherapy for recurrent tumors after potentially curative resection were studied. Gene alterations or polymorphisms were analyzed in DNA from the primary tumor tissue, and the response to radiotherapy was based on the metastatic lesion. Mutations in exons 5-8 of the p53 gene were detected by polymerase chain reaction (PCR)-single strand conformation polymorphism (SSCP) analysis. p21 gene polymorphisms were identified by restriction digestion (BsmAI or PstI) of PCR products. Mutations in p53 were found in 13 of 34 patients (38.2%). The response rates (complete plus partial) were 15.4% for patients with tumors having p53 mutations and 61.9% for patients with wild-type p53 (P = 0.013). There was no significant difference between p21 polymorphisms and response to radiation. p53 gene mutations predict response to radiotherapy in NSCLC. Our results provide clinical support for the in vitro model that loss of p53 function decreases radiosensitivity.
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PMID:p53 mutations predict non-small cell lung carcinoma response to radiotherapy. 1009 28

The eukaryotic cell cycle is regulated by a family of serine/threonine protein kinases known as cyclin-dependent kinases (CDKs). The activation of a CDK is dependent on its association with a cyclin regulatory subunit. The formation of distinct cyclin-CDK complexes controls the progression through the first gap phase (G(1)) and initiation of DNA synthesis (S phase). These complexes are in turn regulated by protein phosphorylation and cyclin-dependent kinase inhibitors (CKIs). Cyclin E2 has emerged as the second member of the E-type cyclin family. Cyclin E2-associated kinase activity is regulated in a cell cycle dependent manner with peak activity at the G(1) to S transition. Ectopic expression of cyclin E2 in human cells accelerates G(1), suggesting that cyclin E2 is rate limiting for G(1) progression. Although the pattern and level of cyclin E2 expression in some primary tumor and normal tissue RNAs are distinct from cyclin E1, both E-type cyclins appear to have inherent functional redundancies. This functional redundancy has facilitated the rapid characterization of cyclin E2 and uncovered unique features associated with each E-type cyclin.
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PMID:Cyclin E2, the cycle continues. 1185 29

Reduced expression of the p16 gene product (protein), an inhibitor of cyclin-D-dependent protein kinase which regulates cell cycle at the G1/S boundary, is implicated in tumor progression in various neoplasms. Hypermethylation of the p16 promoter gene has recently been suggested to be one of the reasons for the reduced protein expression. To explore the role of p16 in the biological behavior of adenoid cystic carcinomas (ACC), we investigated the immunohistochemical expression of p16 protein in 38 ACC tumors (32 primary, 3 recurrent, and 3 metastatic tumors) and the methylation status of its promoter gene. We also examined their relationships to the histological grade of malignancy. Positive reaction of p16 protein was demonstrated in the nuclei of luminar cuboidal cells in areas with tubular patterns. The reactions were reduced in the areas with solid or large cribriform patterns. The levels of p16 expression correlated with the histological grade of malignancy. Recurrent or metastatic tumors did not differ with respect to histological grades from the original tumor except for 1 case, in which p16 expression was reduced compared to the primary tumor. Methylation-specific PCR demonstrated the hypermethylation status of the p16 promoter gene in 4 of 22 primary tumors (21%), all of which showed negative or low expression of the p16 protein. The study indicated that p16 expression was reduced in ACC cases of higher histological grade of malignancy and that hypermethylation of its promoter gene may be involved in its process in some cases.
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PMID:Expression of p16 protein and hypermethylation status of its promoter gene in adenoid cystic carcinoma of the head and neck. 1262 3

The genetic mechanisms that control proliferation of childhood musculoskeletal malignancies, notably Ewing's tumor (ET) and rhabdomyosarcoma (RMS), remain largely unknown. Most human cancers appear to overexpress at least one of the G1 cyclins (cyclins D1, D2, D3, E1, and E2) to bypass normal regulation of cell cycle G1 progression. We compared the gene expression profiles of 7 ET and 13 RMS primary tumor samples and found overexpression of cyclin D1 in all 7 ET samples. In contrast, RMS samples expressed higher levels of cyclin D2, cyclin D3, and cyclin E1. This was confirmed by quantitative reverse transcription-polymerase chain reaction and Western blot. The relative roles of RAS-extracellular signal-regulated kinase 1/2 and phosphatidylinositol 3'-kinase (PI3K)-AKT pathways in the regulation of D-type cyclin expression in these tumors were then assessed. Inhibition of either pathway reduced expression of cyclins D1, D2, and D3 in RMS lines, whereas only PI3K inhibitors blocked cyclin D1, D2, and D3 expression in ET lines. Furthermore, PI3K-AKT appeared to regulate D-type cyclin transcription in RMS lines through FKHR and FKHRL1. Finally, the role of the ET-associated EWS-FLI1 fusion gene in regulating D cyclin expression was studied. Inhibition of EWS-FLI1 expression in the TC71 ET line decreased cyclin D1 levels but increased cyclin D3 levels. In contrast, induction of EWS-FLI1 expression in the RD RMS cell line increased cyclin D1 expression but decreased cyclin D3 expression. Our results demonstrate distinct regulation of D-type cyclins in ET and RMS and indicate that EWS-FLI1 can modulate the expression of D-type cyclins independent of cellular backgrounds.
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PMID:Selective usage of D-Type cyclins by Ewing's tumors and rhabdomyosarcomas. 1534 83

In this study, we establish an MCF-7 xenograft model that mimics the progression of human breast carcinomas typified by loss of p53 integrity, development of centrosome amplification, acquired estrogen receptor (ERalpha) heterogeneity, overexpression of Mdm2 and metastatic spread from the primary tumor to distant organs. MCF-7 cells with abrogated p53 function (vMCF-7(Dnp53)) maintained nuclear ERalpha expression and normal centrosome characteristics in vitro. However, following mitogen stimulation, they developed centrosome amplification and a higher frequency of aberrant mitotic spindles. Centrosome amplification was dependent on cdk2/cyclin activity since treatment with the small molecule inhibitor SU9516 suppressed centriole reduplication. In contrast to the parental MCF-7 cells, when introduced into nude mice as xenografts, tumors derived from the vMCF-7(DNp53) cell line developed a strikingly altered phenotype characterized by increased tumor growth, higher tumor histopathology grade, centrosome amplification, loss of nuclear ERalpha expression, increased expression of Mdm-2 oncoprotein and resistance to the antiestrogen tamoxifen. Importantly, while MCF-7 xenografts did not develop distant metastases, primary tumors derived from vMCF-7(DNp53) cells gave rise to lung metastases. Taken together, these observations indicate that abrogation of p53 function and consequent deregulation of the G1/S cell cycle transition leads to centrosome amplification responsible for breast cancer progression.
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PMID:Impaired p53 function leads to centrosome amplification, acquired ERalpha phenotypic heterogeneity and distant metastases in breast cancer MCF-7 xenografts. 1826 35


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