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

The transcription factor E2F has been implicated in cell cycle control by virtue of its association with cyclins, cyclin-dependent kinases, and pRb-related tumor suppressor gene products. Eggs and embryos from the frog Xenopus laevis have been used to investigate the characteristics of E2F-like molecules in the Xenopus cell cycle and throughout early development. We find multiple E2F species in Xenopus eggs, at least one of which is modified by phosphorylation. The vast majority of E2F remains in the free form throughout the very early embryonic cell cycle, and it also remains predominantly free until some time after the mid-blastula transition, the onset of zygotic transcription. At this time, E2F complexes significantly to pRb but not to cdk2, although cdk2 binding is found in tissue culture cells from a very advanced stage in embryogenesis. This suggests that the complexing of E2F to cyclins, cyclin-dependent kinases, and tumor suppressor gene products may be controlled separately in early Xenopus development. Thus, the association of E2F with other molecules may not result solely from processes affecting cell cycle progression but may also reflect developmental and differentiation cues.
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PMID:E2F and its developmental regulation in Xenopus laevis. 800 93

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

The cyclin-dependent kinases and their associated regulatory cyclins control cell cycle progression and cell growth. Antibodies against these proteins were used to determine their levels in several lung tumor-derived cell lines and a "normal" immortalized bronchoepithelial cell line in order to investigate their potential roles in the etiology of lung cancer. All the cell lines expressed roughly equal levels of cdk-1; cdk-2; PSTAIRE-sequence containing kinases; proliferating cell nuclear antigen; and cyclins A, B1, and E. Cyclin D1, however, was present at 4- to 100-fold higher levels in 11 of 12 non-small cell lung cancer cell lines than in the bronchoepithelial line and all but one of the small cell lung cancer lines. Furthermore, immunoblots of the retinoblastoma gene product, pRB, revealed a perfect correlation between pRB levels and tumor type with normal levels of phosphorylation-competent pRB in all of the non-small cell lung cancer lines and undetectable levels of pRB in all of the small cell lung cancer lines. These data suggest the possibility that small cell and non-small cell lung cancer may evade normal growth controls by different mechanisms: loss of the proliferation inhibitor pRB in small cell lung cancer and overexpression of the growth promoting cyclin D1 in non-small cell lung cancer.
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PMID:Cyclin D1 overexpression vs. retinoblastoma inactivation: implications for growth control evasion in non-small cell and small cell lung cancer. 805 67

Several members of the cdk family of protein kinases are involved in the regulation of the eukaryotic cell cycle. Using a PCR-based strategy we have screened different human tumor cell lines for cdk-related cDNAs. One clone isolated from the bladder carcinoma cell line RT112 encodes a novel protein kinase named PISSLRE, based on its predicted sequence at the conserved PSTAIRE motif. PISSLRE showed 50% amino acid identity with the previously isolated p58KGTA. PISSLRE contained all the structural elements featured by cyclin dependent kinases, including a proline in the PSTAIRE motif, which might be important for cyclin binding. PISSLRE was found expressed as 2.0 kb messenger RNA in a variety of human cell lines. Its expression was not restricted to tumor cells as it was detectable also in normal fibroblasts. In adult tissues, PISSLRE mRNA showed the highest expression in lung, liver and kidney. The broad expression pattern in adult tissues might suggest that PISSLRE could be involved in processes distinct from cell proliferation.
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PMID:Molecular cloning of PISSLRE, a novel putative member of the cdk family of protein serine/threonine kinases. 808 11

Proliferating cell nuclear antigen (PCNA)/cyclin is currently often investigated immunohistochemically in tumors as a marker of cell proliferation, but many problems remain open concerning its reliability as a prognostic factor. PCNA has been studied in a series of 123 brain tumors using the monoclonal antibody PC10. A clear intra- and inter-tumor variability of PCNA-positive nuclei has been found, but taking into account the tumor areas with the highest number of positive nuclei, a positive correlation between this number and the histological malignancy of tumors has been demonstrated. The staining intensity of nuclei was variable; very-intensely positive nuclei, counted separately, are hypothesized to represent nuclei in S-phase of the cell cycle. In ependymomas the investigation included a quantitative statistical analysis. The number of PCNA-positive nuclei correlated with cell density and mitotic index, but only very intensely positive nuclei showed a significant statistical correlation with survival. In spite of the many possibilities of wrong interpretation of PCNA expression, the most important of which is its deregulation, the method is useful in the practice for prognostic purposes. Its important advantages are the possibility of a retrospective application and a visual analysis of the proliferation potential of tumors.
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PMID:Proliferating cell nuclear antigen expression in brain tumors, and its prognostic role in ependymomas: an immunohistochemical study. 809 64

In normal human diploid fibroblasts, cyclins of the A, B, and D classes each associate with cyclin-dependent kinases (CDKs), proliferating cell nuclear antigen (PCNA), and p21, thereby forming multiple independent quaternary complexes. Upon transformation of diploid fibroblasts with the DNA tumor virus SV40, or its transforming tumor antigen (T), the cyclin D/p21/CDK/PCNA complexes are disrupted. In transformed cells, CDK4 totally dissociates from cyclin D, PCNA, and p21 and, instead, associates exclusively with a polypeptide of 16 kD (p16). Quaternary complexes containing cyclins A or B1 and p21/CDK/PCNA also undergo subunit rearrangement in transformed cells. Both PCNA and p21 are no longer associated with CDC2-cyclin B1 binary complexes. Cyclin A complexes no longer contain p21, and a new 19-kD polypeptide (p19) is found in association with cyclin A. The pattern of subunit rearrangement of cyclin-CDK complexes in SV40-transformed cells is also shared in those containing adeno- or papilloma viral oncoproteins. Rearrangement also occurs in p53-deficient cells derived from Li-Fraumeni patients that carry no known DNA tumor virus. These findings suggest a mechanism by which oncogenic proteins alter the cell cycle of transformed cells.
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PMID:Subunit rearrangement of the cyclin-dependent kinases is associated with cellular transformation. 810 26

Staurosporine (SSP) is an inhibitor of a variety of protein kinases with an especially high affinity towards protein kinase C. Whereas SSP has been shown to halt the cell cycle progression of various normal, nontransformed cell types in G1, most virus transformed or tumor cells are unaffected in G1 but arrest in G2 phase. SSP has also been observed to increase the appearance of cells with higher DNA content, suggestive of endoreduplication, in cultures of tumor cells. Using multivariate flow cytometry (DNA content vs. expression of cyclin B, nuclear p120 protein, or protein reactive with Ki-67 antibody) which makes it possible to discriminate cells with identical DNA content but at different phases of the cycle, we have studied the cell cycle progression of human lymphocytic leukemic MOLT-4 cells in the presence of 0.1 microM SSP. MOLT-4 cells did not arrest in G1 or G2 phase in the presence of the inhibitor. Rather, they failed to undergo cytokinesis, entering G1 phase at higher DNA ploidy (tetraploidy; G1T), and then progressed through ST (rereplication) into G2T and MT. The rates of entrance to G2 and G2T were essentially identical, indicating that the rates of cell progression through S and ST as well as through G2 and G2T, respectively, were similar. Cells entrance to mitosis and mitotic chromatin condensation were also similar at the diploid and tetraploid DNA content level and were unaffected by 0.1 microM SSP. No evidence of growth imbalance (altered protein or RNA to DNA ratio) was observed in the case of tetraploid cells. The data show that, in the case of MOLT-4 cells, all events associated with the chromosome or DNA cycle were unaffected by SSP; the only target of the inhibitor appears to be kinase(s) controlling cytokinesis.
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PMID:Effect of staurosporine on MOLT-4 cell progression through G2 and on cytokinesis. 812 77

Tumor formation results from alterations in the control of normal cell proliferation. To further our understanding of the molecular mechanisms underlying the deregulation of cell proliferation much attention, over the past decade, has been focused on the function of proto-oncogenes. Cellular oncogenes are thought to be growth promoting. More recently, a class of genes known as tumor suppressors have come under intense study. Tumor suppressors are largely thought to restrain cell proliferation. The retinoblastoma protein (Rb) is one of a growing list of tumor suppressors. Concurrent with the study of tumor suppressor genes has been a rapid increase in our understanding of the cell cycle at the molecular level. Rb and a related protein p107 are involved in the processes of cell proliferation and differentiation. Each functionally interacts with and affects the activity of the transcription factor E2F as well as other transcription factors involved in cell proliferation and differentiation. Additionally, Rb and p107 are modified by, and/or form specific complexes with, several elements of the basic cell cycle machinery. Specifically, Rb and p107 interact with and are modified by various cyclins and cyclin dependent kinases (cdk), some of which have been shown to be essential for cell cycle progression and in some cases their deregulation has been implicated in the development of cancer. This review will attempt to convey our current functional and mechanistic understanding of the biological roles Rb and p107 play in proliferation, development and differentiation. A knowledge of the interplay between these positive and negative regulators of cell proliferation and differentiation, noted above, is central to our understanding of human cancer.
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PMID:The cell cycle and the retinoblastoma protein family. 814 45

The mutation of tumor suppressor genes is thought to contribute to tumor growth by inactivating proteins that normally act to limit cell proliferation. Several tumor suppressor proteins have been identified in recent years, but only two of them, p53 and pRb, are understood in detail. In the past year, a role has become apparent for both of these proteins in transcription and phosphorylation events required for passage of a cell from G1 to S phase. The pRb protein appears to prevent the function of transcription factors and other proteins needed for S phase until its inactivation by cyclin-dependent kinases in late G1. Induction of p53 by DNA damage may act to cause cell cycle arrest or cell death by altering the transcription program of damaged cells. A detailed molecular understanding of these growth regulators is now emerging, and is the subject of this review.
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PMID:Tumor suppressor genes. 819 33

D-type cyclins are necessary and rate-limiting for G1 progression during the mammalian cell cycle. Cyclins D1, D2, and D3 are encoded by distinct genes and are expressed in proliferating cells in a lineage-specific manner. Monoclonal antibodies (mAbs) generated to bacterially produced recombinant D-type cyclins were able to react with the native proteins expressed in mammalian cells. One mouse and three rat mAbs immunoprecipitated cyclin D1 from mouse macrophages. Only rat mAbs reacted with human cyclin D1 and cross-reacted with cyclin D2 expressed in proliferating T lymphocytes and human tumor cell lines. A single rat mAb to cyclin D2 exhibited a pattern of reactivity reciprocal to that of rat mAbs to D1. Three rat mAbs reacted specifically with mouse or human cyclin D3, but did not cross-react with cyclins D1 or D2 from either species. Representative mAbs were useful for immunoblotting and detected D-type cyclins coprecipitating in complexes recovered with antiserum to cyclin-dependent kinase-4 (CDK4). Because these mAbs detect D-type cyclins in the nuclei of fixed permeabilized cells, they should prove useful in documenting cyclin overexpression in those human tumors in which the genes are amplified or are targets of specific chromosomal rearrangements.
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PMID:Monoclonal antibodies to mammalian D-type G1 cyclins. 820 Jun 57


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