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)

Cyclin and cyclin-dependent kinase (CDK) complexes play important roles in controlling the cell cycle. The CDK inhibitors (CDKIs) inhibit the kinase activities of the complexes and block transitions of the cell cycle. Recently several CDKI genes have been cloned, and evidence suggests that at least a couple of these may be tumor suppressor genes. In this study, the partial structure of a CDKI gene, p27/Kip1, was determined. In addition, a large number of human cancers (432 cases) and cancer cell lines (20 lines) were analyzed for alterations of the p27/Kip1 gene by Southern blot analysis and PCR/single-strand conformation polymorphism. The coding region of the p27/Kip1 gene consists of at least two exons and an intron of about 600 bp. In 140 tumors of various tissues and 18 transformed cell lines, no deletions or rearrangements of the gene were detected by Southern blot analysis using a part of the coding sequence as a probe. One polymorphism and one silent mutation were detected by PCR/single-strand conformation polymoprhism. The polymorphism was a nucleotide substitution of guanine for thymine (GTC-->GGC) at codon 109, resulting in an amino acid substitution of glycine for valine (Val-->Gly). In summary, no abnormalities of the p27/Kip1 gene were detected in human malignancies. Now, two groups of CDKIs are classified based on the structure of the proteins. One group includes the p15, p16, and p18 CDKIs, which have ankyrin repeat motifs. The p15 and p16 CDKI genes are very frequently mutated in a variety of cancers. The p27/Kip1 and p21 CDKIs belong to the other group. We reported previously that abnormalities of the p21 gene were very rare. The latter group of the CDKIs, including p27/Kip1 and p21, are rarely mutated in human malignancies.
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PMID:Molecular analysis of the cyclin-dependent kinase inhibitor gene p27/Kip1 in human malignancies. 775 74

The p27Kip1 gene codes for a cyclin-dependent kinase inhibitor implicated in G1 arrest by transforming growth factor beta, cell-cell contact, agents that elevate cyclic AMP, and the growth-inhibitory drug rapamycin. p27 binds to and inhibits complexes formed by cyclin E-cdk2, cyclin A-cdk2, and cyclin D-cdk4. The involvement of p27 in the negative regulation of cell proliferation suggests that it may also function as a tumor suppressor gene. Using a combination of somatic cell hybrid panels and fluorescence in situ hybridization p27Kip1 has been mapped to the short arm of chromosome 12 at the 12p12-12p13.1 boundary, reported to harbor deletions and rearrangements in leukemia and mesotheliomas. In order to assess potential p27Kip1 gene alterations, we have screened a total of 147 human primary solid tumors and found no detectable cancer-specific mutations. These results argue that the often observed loss of antimitogenic transforming growth factor beta responsiveness in human cancer cells is not due to structural defects in p27Kip1.
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PMID:p27Kip1: chromosomal mapping to 12p12-12p13.1 and absence of mutations in human tumors. 788 10

The prevalence of feline leukemia virus (FeLV) antigen and DNA was assessed in formalin-fixed, paraffin-embedded tumor tissues from 70 cats with lymphosarcoma (LSA). Tissue sections were tested for FeLV gp70 antigen using avidinbiotin complex (ABC) immunohistochemistry (IHC); DNA was extracted and purified from the same tissue blocks for polymerase chain reaction (PCR) amplification of a 166 base pair region of the FeLV long terminal repeat (LTR). Results were related to antemortem FeLV enzyme-linked immunosorbent assay (ELISA) for serum p27 antigen, anatomic site of LSA, and patient age. Viral DNA was detected by PCR in 80% of cases and viral antigen by IHC in 57% of cases. Seventeen cases were PCR-positive and IHC-negative; one case was PCR-negative and IHC-positive. Clinical records included FeLV ELISA results for 30 of 70 cats. All 19 ELISA-positive cats were positive by PCR and IHC; of the 11 ELISA-negative cats that were negative by IHC, seven were positive by PCR. When evaluated according to anatomic site, FeLV DNA and antigen were detected less frequently in intestinal LSAs than in multicentric and mediastinal tumors. Lymphosarcoma tissues from cats < 7 yr were several fold more likely to be positive for FeLV antigen by IHC than were tumors from cats > or = 7 yr. However, there was no significant difference in PCR detection of FeLV provirus between LSAs from cats < 7 yr and those > or = 7 yr.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Feline leukemia virus detection by immunohistochemistry and polymerase chain reaction in formalin-fixed, paraffin-embedded tumor tissue from cats with lymphosarcoma. 826 65

A new complementary DNA, p27, has been cloned and sequenced from estradiol-treated MCF7 human breast carcinoma cells. It encodes a putative highly hydrophobic protein of 122 amino acids which has a 33% overall sequence similarity to the product of the 6-16 gene (R. L. Friedman, S. P. Manly, M. McMahon, I. M. Kerr, and G. R. Stark, Cell, 38: 745-755, 1984), which is transcriptionally induced by interferons of the alpha/beta type. We demonstrate here that the p27 gene, which is located in band q32 of human chromosome 14, is also induced by interferon-alpha in human cell lines of different origin and that expression is independent of the presence of estradiol receptor in the cells. High levels of p27 RNA were found in vivo in approximately 50% of primary human breast carcinomas (21 were tested by Northern blotting). In situ hybridization to some of the p27-overexpressing tumors showed that the p27 RNA is localized in cancer cells and sometimes also in fibroblastic cells of tumor stroma. p27 RNA levels in the tumors did not correlate with the presence of estrogen receptor or with the expression of the estrogen-induced pS2 gene. Further studies are now necessary to elucidate the cause of p27 gene overexpression in breast carcinoma and in particular to determine whether it corresponds to chromosomal rearrangements in the 14q32 region and/or to induction by interferons of the alpha/beta type.
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PMID:Identification of a new interferon-alpha-inducible gene (p27) on human chromosome 14q32 and its expression in breast carcinoma. 835 38

The p27/Kip1 protein belongs to the recently identified family of proteins called cyclin-dependent kinase inhibitors. These proteins play an important role as negative regulators of cell cycle-dependent kinase activity during progression of the cell cycle. Since cyclin-dependent kinase inhibitors can inhibit cell proliferation, they may have a role as tumor suppressor genes. To determine whether p27 alterations may be involved in tumorigenesis, we examined its mutational status in 36 primary breast carcinomas and 9 breast cancer cell lines using PCR-single-strand conformational polymorphism, direct DNA sequencing, and Southern blot analysis. Southern blot analysis showed no homozygous deletions of the p27 gene in either the clinical samples or cell lines. Two point mutations were found in primary tumors. One represents a previously undescribed polymorphism at codon 142; another is a nonsense mutation at codon 104. The latter mutation was absent in the normal matched control sample, and, in addition, it was accompanied with the loss of heterozygosity (LOH) of a microsatellite marker in the vicinity of the p27 gene on chromosome 12p13. These data indicate that p27 mutations are a rare event in breast cancer, but may play an important role in the development of a minority of these cancers. Furthermore, LOH analysis of the 12p13 locus revealed that an additional four of six matched DNA samples had LOH at 12p13 but did not have an alteration of the p27 gene, suggesting that another tumor suppressor gene is located on the short arm of human chromosome 12 which may be frequently involved in the pathogenesis of breast cancers.
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PMID:p27/Kip1 mutation found in breast cancer. 862 18

While oncoproteins encoded by small DNA tumor viruses and Epstein-Barr virus (EBV) latent antigens facilitate G1/S progression, the EBV lytic switch transactivator Zta was found to inhibit growth by causing cell cycle arrest in G0/G1 in several epithelial tumor cell lines. Expression of Zta results in induction of the tumor suppressor protein, p53, and the cyclin-dependent kinase inhibitors, p21 and p27, as well as accumulation of hypophosphorylated pRb. Up-regulation of p53 and p27 occurs by post-transcriptional mechanisms while expression of p21 is induced at the RNA level in a p53-dependent manner. Inactivation of pRb by transient overexpression of the human papillomavirus E7 oncoprotein indicates that pRb or pRb-related proteins are key mediators of the growth-inhibitory function of Zta. These findings suggest that EBV plays an active role in redirecting epithelial cell physiology to facilitate the viral replicative program through a Zta-mediated growth arrest function.
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PMID:The Epstein-Barr virus bZIP transcription factor Zta causes G0/G1 cell cycle arrest through induction of cyclin-dependent kinase inhibitors. 865 72

We have isolated human cDNA and genomic clones of a gene termed p57KIP2, which is related to the p2I WAFI and p27 KIP1 genes that encode inducible inhibitors of cyclin-dependent kinase activity. The p57 gene contains three GC-rich introns of 166 bp, 566 bp, and 83 bp, and two of the four exons correspond to coding regions. Alternative splicing generates the heterogeneity in the translational initiations. As this gene has been localized to chromosomal band 11pI5.5, a region thought to be the location of a tumor suppressor gene(s) for carcinomas of the breast, bladder, and liver, we have examined a large number of tumors for genetic alterations of p57. Although no somatic mutation has been detected, we have found several normal variations in this gene, including four types of 12-bp in-frame deletions in the proline/alanine repeating domain, in which nearly 40 motifs, viz., 5'-CCGGCC-3', are tandemly repeated.
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PMID:Characterization of the human p57KIP2 gene: alternative splicing, insertion/deletion polymorphisms in VNTR sequences in the coding region, and mutational analysis. 865 43

The cyclin-dependent kinase (CDK) inhibitor p21 is induced by the tumor suppressor gene product p53 and is thought to be important for the arrest of the cell cycle following DNA damage. Here we have investigated the contribution of p21 in inhibiting different cyclin-CDK complexes that drive different cell cycle transitions following UV irradiation-induced DNA damage in normal human fibroblasts and immortalized rodent fibroblasts. When cells were exposed to a low dose of UV irradiation, both p53 and p21 were induced; the protein kinase activities associated with Cdc2, Cdk2, and Cdk4 were inhibited; and there was a good correlation between their inhibition and binding to p21. p21 alone is likely to be sufficient for the inhibition of Cdk2 because all the cyclin-complexed forms of Cdk2 were associated with p21 after irradiation. In contrast, only a small proportion of Cdk4 and Cdc2 was complexed with p21, although the level of Cdk4 associated with either p21 or p27 was increased after irradiation. Furthermore, recombinant p21 added to an unirradiated cell lysate at the same level as that induced by irradiation damage inhibited only the kinase activity associated with Cdk2. Cdc2 is likely to be inhibited by Thr-14/Tyr-15 phosphorylation after irradiation because Cdc2 was tyrosine-phosphorylated, and recombinant Cdc25 was able to increase its kinase activity significantly. Taken together, these results suggest that different CDKs are inhibited by different mechanisms following UV-induced DNA damage: Cdk2 is inhibited by the elevated level of p21; Cdk4 is inhibited by cooperation of p21 with other CDK inhibitors, like p27, and possibly by phosphorylation; and Cdc2 is inhibited by Thr-14/Tyr-15 phosphorylation. It is likely that these underlying mechanisms that inactivate CDKs are similar for other kinds of DNA damage.
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PMID:Cyclin-dependent kinases are inactivated by a combination of p21 and Thr-14/Tyr-15 phosphorylation after UV-induced DNA damage. 866 25

The mechanisms of cytotoxic killing of various tumor cell lines and immunodeficiency virus-infected T cell lines by simian gamma delta T cells were examined. The lysis of the majority of the target cell lines by gamma delta effectors was calcium-dependent, indicating that cytotoxicity is mediated by the perforin/granzyme pathway rather than the Fas-FasL pathway, with the exception of Jurkat cells. The gamma delta T cells were able to suppress SIV replication as measured by the p27 ELISA and the suppression was contact-dependent. We further determined that the target cells were induced to undergo apoptosis by the gamma delta T cell effectors. These results contribute to our understanding of the function of simian gamma delta T cells and their similarities to human gamma delta T cells, and extend our knowledge on the cytotoxic mechanisms employed by gamma delta T cells in general.
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PMID:Mechanisms of simian gamma delta T cell cytotoxicity against tumor and immunodeficiency virus-infected cells. 873 16

We have developed an animal tumor model system to study the effects of c-Myc activation on apoptosis induction in vivo. Tumors were generated in SCID mice from Rat-1 fibroblasts that constitutively express an inactive c-Myc-estrogen receptor fusion protein (T.D. Littlewood et al, Nucleic Acids Res., 23: 1686 -1690, 1995), which is activated in vivo by the administration of 4-hydroxytamoxifen in time release pellets. We demonstrate that activation of c-Myc results in a substantial increase in the number of apoptotic tumor cells and that this apoptosis is predominant in regions of tumor hypoxia. c-Myc-induced apoptosis of hypoxic cells is inhibited in tumors that overexpress the human Bcl-2 protein. Bcl-2, however, does not prevent p53 protein accumulation or the down-regulation of the cyclin-cdk inhibitor p27 protein following c-Myc activation by 4-hydroxytamoxifen. This result suggests that Bcl-2 does not affect c-Myc function directly but acts downstream of c-Myc to inhibit apoptosis. We propose that the ability of activated c-Myc to enhance cellular proliferation might contribute to the genesis of early neoplasms that are held in check by the alternate ability of c-Myc to induce apoptosis of cells that have outgrown their supply of oxygen or other factors associated with hypoxic regions of solid tumors. Secondary genetic lesions downstream of c-Myc that suppress the apoptotic potential of tumor cells, such as Bcl-2 overexpression, might play an important role in the malignant progression of these tumors because they would disrupt the balance between apoptosis and proliferation initiated by c-Myc deregulation.
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PMID:Modulation of c-Myc activity and apoptosis in vivo. 881 14


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