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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The cell cycle regulatory tumor suppressor proteins p53 and pRB are targeted for inactivation by several tumor viruses, including the high-risk types of human papillomaviruses (HPVs) via interactions of the HPV E6 and E7 oncoproteins with p53 and pRB, respectively. p53 plays a central role in a signal transduction pathway that mediates G1 arrest after DNA damage, though the mechanism by which G1 arrest occurs has not been elucidated. The cyclin-associated protein p21waf1/cip1 has recently been shown to be induced by p53 and to inhibit cyclin complex-mediated phosphorylation of pRB in vitro. Thus, we investigated a possible role for pRB in the p53-mediated DNA damage response. After gamma-irradiation, cells expressing wild-type p53 arrested in G1, contained increased levels of WAF1/CIP1 mRNA, and demonstrated accumulation of hypophosphorylated pRB. In contrast, cell lines with abnormal p53 genes or with p53 functionally inactivated by the E6 oncoprotein of HPV16 (a high-risk HPV) failed to arrest in G1, did not elevate WAF1/CIP1 mRNA, and did not accumulate hypophosphorylated pRB. Despite apparently normal elevation of p53 protein and WAF1/CIP1 mRNA after irradiation, cells expressing HPV16 E7 also failed to arrest in G1 and did not accumulate hypophosphorylated pRB. Disruption of RB genes alone did not totally abrogate this G1 arrest. Our results suggest that p53 indirectly regulates phosphorylation of pRB and that pRB and/or other pRB-like molecules that bind to HPV16 E7 participate in the DNA damage-mediated G1 arrest signal. In the process of HPV infection, the HPV E6 and E7 oncoproteins may undermine this cell cycle checkpoint, contributing to the accumulation of genetic alterations during tumorigenesis.
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PMID:p53-dependent G1 arrest involves pRB-related proteins and is disrupted by the human papillomavirus 16 E7 oncoprotein. 820 87

The methods of cell cycle analysis that rely on DNA content measurements cannot discriminate between cells at different phases of the cycle if these cells have similar DNA content. This limitation can be circumvented by measurement of another cell cycle phase-specific cell constituent in addition to DNA content, followed by bivariate analysis of the correlated data. The aim of the present study was to explore the utility of a monoclonal antibody against the G2- and M phase-specific regulatory protein cyclin B for discrimination of cell populations with overlapping DNA content. This analysis, which was based on correlated DNA/cyclin B content measurements by flow cytometry, was applied to human lymphocytic leukemic MOLT-4 cells. The onset of cyclin B synthesis was observed in the last one third of S phase with its maximum accumulation in G2 and M phases; cells in G1 and early- and mid-S phases were negative. Cells arrested in metaphase by vinblastine expressed high levels of this protein, although not as high as in cells arrested in G2 by the DNA topoisomerase II inhibitor m-AMSA. Disruption of cytokinesis by the protein kinase inhibitor staurosporine led to DNA rereplication, cell progression through the chromatin cycle at higher DNA ploidy, and induction of polyploidy. It was possible, utilizing the cyclin B antibody, to discriminate between G2 + M cells with a 2C level of DNA and G1 cells with 4C DNA, as well as to distinguish doublets of G1 cells with a 2C DNA level. Thus, the rate of cell entrance to G1 at the 4C DNA level and the rates of progression through the cycle at both the 2C and 4C DNA levels could be simultaneously estimated. The data indicate that, in the presence of 0.1 microM staurosporine, cytokinesis of all MOLT-4 cells is impaired and the cells enter to and progress through the chromosome cycle at 4C DNA at the same rates as at 2C DNA. This approach can be helpful in the analysis of DNA ploidy and the cell cycle of human tumors when there is an overlap in DNA content values between normal stromal or infiltrating cells and aneuploid tumor cell population and may be the method of choice to investigate the activity of antitumor drugs which impair cytokinesis but do not interfere with progression of cells through the chromatin cycle.
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PMID:Simultaneous analysis of cell cycle kinetics at two different DNA ploidy levels based on DNA content and cyclin B measurements. 822 43

Cyclin D1, a putative G1 cyclin, has been implicated in cell cycle control. The human cyclin D1 gene is located on chromosome 11q13 where DNA rearrangement and amplification have been detected in several types of human cancer. Previous studies demonstrated that the cyclin D1 gene is not only rearranged or amplified but also overexpressed in some of these human tumors and tumor-derived cell lines. To further address the roles of cyclin D1 in cell cycle control and tumorigenesis, we have stably overexpressed the human cyclin D1 cDNA in Rat6 embryo fibroblasts by using retrovirus mediated transduction. The cyclin D1 protein was overproduced about 10-fold and was localized predominately in the nucleus. Cyclin D1 overexpressing cells displayed a decrease in the duration of the G1 phase, decreased cell size, and induced tumors when injected into athymic (nude) mice. In addition, overexpression of cyclin D1 in Rat6 cells perturbed the expression of several cellular growth-related genes including c-myc, c-jun, and cyclin A, but not cyclin D3. Taken together, these results indicate that deregulated expression of the cyclin D1 gene can cause disturbances in cell cycle control and gene expression and also enhance tumorigenesis.
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PMID:Overexpression of cyclin D1 in rat fibroblasts causes abnormalities in growth control, cell cycle progression and gene expression. 824 50

Cyclin A associates with both the p34 cdc2 and p33 cdk2 kinases and is involved at two major check-points (G1-S and G2-M) of the cell cycle. The cyclin has been identified in multimeric protein complexes that incorporate the E2F transcription factor, the p33 cdk2 kinase, and p107, which is related to the retinoblastoma protein. Therefore, cyclin A provides a link between studies on the cell-cycle machinery and those aiming to elucidate the modulation of cell proliferation and regulation of gene expression by oncogenes and growth-suppressor proteins. The modification of cyclin A expression in a human liver cancer by the insertion of hepatitis B viral DNA into the cyclin A gene, and binding of cyclin A to the oncogenic E1A viral protein in adenovirus-infected cells suggest that the cyclin is implicated in human carcinogenesis. In addition, cyclin A might also be considered as a marker for tumor-cell proliferation in oncology. With these views in mind, it is now important to extend these observations to other types of cancer.
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PMID:Oncogenic activation of cyclin A. 838 33

A mutant simian virus 40 (SV40) large tumor (T) antigen bearing alanine instead of threonine at residue 124 (T124A) failed to replicate SV40 DNA in infected monkey cells (J. Schneider and E. Fanning, J. Virol. 62:1598-1605, 1988). We investigated the biochemical properties of T124A T antigen in greater detail by using purified protein from a baculovirus expression system. Purified T124A is defective in SV40 DNA replication in vitro, but does bind specifically to the viral origin under the conditions normally used for DNA replication. The mutant protein forms double-hexamer complexes at the origin in an ATP-dependent fashion, although the binding reaction requires somewhat higher protein concentrations than the wild-type protein. Binding of T124A protein results in local distortion of the origin DNA similar to that observed with the wild-type protein. These findings indicate that the replication defect of T124A protein is not due to failure to recognize and occupy the origin. Under some conditions T124A is capable of unwinding short origin DNA fragments. However, the mutant protein is almost completely defective in unwinding of circular plasmid DNA molecules containing the SV40 origin. Since the helicase activity of T124A is essentially identical to that of the wild-type protein, we conclude that the mutant is defective in the initial opening of the duplex at the origin, possibly as a result of altered hexamer-hexamer interactions. The phenotype of T124A suggests a possible role for phosphorylation of threonine 124 by cyclin-dependent kinases in controlling the origin unwinding activity of T antigen in infected cells.
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PMID:Mutation of the cyclin-dependent kinase phosphorylation site in simian virus 40 (SV40) large T antigen specifically blocks SV40 origin DNA unwinding. 839 24

Cyclins are prime cell cycle regulators and are central to the control of major check points in eukaryotic cells. The aberrant expressions of two cyclins (i.e., cyclins A and D1) have been observed in some cancers, suggesting they may be involved in loss of growth control. However, in spite of these occasional changes involving only two cyclins, there are no clear connections between general derangements of other cyclins or their dependent kinases in a single tumor type. We detected general cyclin overexpression in 3 of 3 breast tumor tissue samples. In addition, using proliferating normal vs. human tumor breast cells as a model system, we observed a number of alterations in cyclin expression: (i) an 8-fold amplification of cyclin E gene in one tumor line, a 64-fold overexpression of its mRNA, and altered expression of its protein; (ii) deranged expression of cyclin E protein in all (10 of 10) tumor cell lines studied; (iii) increased cyclin mRNA stability, resulting in (iv) general overexpression of RNAs and proteins for cyclins A and B and CDC2 in 9 of 10 tumor lines and (v) deranged order of appearance of cyclins in synchronized tumor vs. normal cells, with mitotic cyclins appearing prior to G1 cyclins. These multiple general derangements in cyclin expression in human breast cancer cells provide evidence linking aberrant cyclin expression to tumorigenesis.
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PMID:Redundant cyclin overexpression and gene amplification in breast cancer cells. 843 82

Recent studies have provided evidence suggesting that disruption of cyclin function may play a critical role in tumorigenesis. Cyclin D1, a putative G1 cyclin previously isolated in human parathyroid adenomas (designated PRAD1) and mouse macrophages (designated Cyl1), has been implicated in various neoplasias including breast and squamous cell carcinomas (SCC). The role of cyclin altered regulation in the different stages of tumor progression has not been studied in a well defined animal model system. In the study presented here, Cyl1 was mapped to the distal end of mouse chromosome 7 and found to be dramatically overexpressed in skin SCC. In premalignant stages of tumor development, early papillomas showed basal Cyl1 transcript levels, whereas over-expression was observed in most advanced papillomas. These findings suggest that altered expression of cyclin D1 plays a critical role in mouse skin carcinogenesis and may be related to the acquisition of autonomous growth by papillomas. Further studies on the role of cyclin D1 in the mouse model system should prove valuable for understanding the multistep basis of tumor progression.
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PMID:Overexpression of cyclin D1 in mouse skin carcinogenesis. 847 37

Originally identified as a 'mitotic cyclin', cyclin A exhibits properties of growth factor sensitivity, susceptibility to viral subversion and association with a tumor-suppressor protein, properties which are indicative of an S-phase-promoting factor (SPF) as well as a candidate proto-oncogene. Other recent studies have identified human cyclin D1 (PRAD1) as a putative G1 cyclin and candidate proto-oncogene. However, the specific enzymatic activities and, hence, the precise biochemical mechanisms through which cyclins function to govern cell cycle progression remain unresolved. In the present study we have investigated the coordinate interactions between these two potentially oncogenic cyclins, cyclin-dependent protein kinase subunits (cdks) and the Rb tumor-suppressor protein. The distribution of cyclin D isoforms was modulated by serum factors in primary fetal rat lung epithelial cells. Moreover, cyclin D1 was found to be phosphorylated on tyrosine residues in vivo and, like cyclin A, was readily phosphorylated by pp60c-src in vitro. In synchronized human osteosarcoma cells, cyclin D1 is induced in early G1 and becomes associated with p9Ckshs1, a Cdk-binding subunit. Immunoprecipitation experiments with human osteosarcoma cells and Ewing's sarcoma cells demonstrated that cyclin D1 is associated with both p34cdc2 and p33cdk2, and that cyclin D1 immune complexes exhibit appreciable histone H1 kinase activity. Immobilized, recombinant cyclins A and D1 were found to associate with cellular proteins in complexes that contain the p105Rb protein. This study identifies several common aspects of cyclin biochemistry, including tyrosine phosphorylation and the potential to interact directly or indirectly with the Rb protein, that may ultimately relate membrane-mediated signaling events to the regulation of gene expression.
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PMID:Two potentially oncogenic cyclins, cyclin A and cyclin D1, share common properties of subunit configuration, tyrosine phosphorylation and physical association with the Rb protein. 847 54

The genetic status of cyclin genes was examined in a panel of 47 colorectal carcinoma cell lines. Cyclin D2 was found to be amplified in one tumor and cyclin E in another. In each of the two cases, the amplified cyclin gene was overexpressed at the protein or mRNA level. Cyclin D1, previously shown to be amplified in breast and other tumors, was not amplified in these cancers. These data suggest that a variety of cyclin genes can play a role in human tumorigenesis and that cyclins D2 and E are particularly important in a subset of colorectal neoplasms.
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PMID:Amplification of cyclin genes in colorectal carcinomas. 848

The t(11;14)(q13;q32) translocation and its molecular counterpart, BCL-1 rearrangement, are consistent features of intermediate lymphocytic lymphoma (ILL). Rearrangement is thought to deregulate the nearby PRAD-1/BCL-1 proto-oncogene that is a newly identified member of the cyclin family. To characterize further the association between rearrangement of chromosome 11q13 and over-expression of BCL-1. Southern blot analysis was performed in 33 cases of ILL, 5 cases of t(11;14)-associated leukemias, and 1 case of leukemia carrying a variant translocation t(11;19)(q13;q13) using three separate BCL-1 locus probes. When RNA was available, BCL-1 expression was assessed by Northern blot analysis. DNA from 19 of 33 ILL (57%) showed BCL-1 rearrangement, 16 involving the major translocation cluster (MTC) region and 3 involving a new breakpoint cluster located in the 5' flanking region of the BCL-1 gene. DNA from 3 of 6 t(11q13)-associated leukemias demonstrated a rearrangement involving the MTC. Northern blot analysis showed that BCL-1 was overexpressed in 14 of 15 ILL and in all leukemias analyzed (included the t(11;19) leukemia) relative to normal and malignant lymphoid tissues. These results constitute additional elements in favor of the role of BCL-1 in lymphoid neoplasia and allow us to speculate about its mechanisms of activation.
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PMID:Rearrangement and overexpression of the BCL-1/PRAD-1 gene in intermediate lymphocytic lymphomas and in t(11q13)-bearing leukemias. 849 40


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