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

The normal cell cycle is regulated by several molecules, such as the tumor-suppressor protein pRb, the G1 cyclins, the cyclin-dependent kinases, and their inhibitors. These regulators are targeted by negative growth regulatory signals, such as that provided by TGF-beta. Here, we show that the presence of either wild-type EBV or its transforming latent membrane protein-1 (LMP-1) results in the loss of TGF-beta 1-mediated growth inhibition in human B cells. Chemical cross-linking with 125I-labeled TGF-beta 1 showed an essentially normal TGF-beta receptor profile in EBV-positive and EBV-negative Burkitt's lymphoma cell lines, and these receptors were shown to be functional in transducing signals, as evidenced by the TGF-beta 1-mediated modulation of junB gene expression. However, TGF-beta 1 did not induce dephosphorylation of pRb in EBV (or LMP-1)-positive cells as opposed to EBV-negative cells, suggesting a dichotomy in the TGF-beta 1 signaling pathway leading to separable gene regulatory and growth inhibitory responses. Furthermore, LMP-1 was found to induce the expression of cyclin D2; normal B cells or EBV-negative Burkitt's lymphoma cells do not express D-type cyclins. Taken together, these data point to a potential mechanism underlying EBV-mediated B cell transformation whereby constitutive induction of key cell cycle regulators by LMP-1 can lead to pRb hyperphosphorylation and uncontrolled cell proliferation.
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PMID:Latent membrane protein-1 induces cyclin D2 expression, pRb hyperphosphorylation, and loss of TGF-beta 1-mediated growth inhibition in EBV-positive B cells. 763 79

Deregulated expression of cyclin D1 occurs in several types of human cancer. Since it often results from a specific chromosomal abnormality, this over-expression is likely to be significant in the development of the disease. Cyclin D1 is also implicated in virally induced tumors in mice and transgenic models based on ectopic expression if cyclin D1 recapitulate features of the naturally occurring tumors. By these criteria, as well as its effects in transfected rodent cells, cyclin D1 has the hallmarks of a cellular proto-oncogene. Although the normal role of cyclin D1 is not well understood, its oncogenic properties appear to involve functional interactions with cyclin-dependent kinases, the retinoblastoma gene product and the MTS1/p16 tumor suppressor gene.
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PMID:Cyclin D1 as a cellular proto-oncogene. 764 9

Several groups have recently isolated and characterized an inhibitor of cyclin-dependent kinases, p21CIP1/WAF1 which is transcriptionally induced by wild-type but not mutant p53. It is likely that p21CIP1/WAF1 mediates the growth suppression effects of p53 by arresting the cell cycle at the G1/S checkpoint, and by inducing apoptosis. To test the hypothesis that primary human tumors have mutations in the CIP1/WAF1 gene which propagates the carcinogenic process, we examined primary breast and sarcoma tumor specimens for alterations in the CIP1/WAF1 gene. Unique, or acquired somatic mutations were not observed indicating that they are not selected for during the carcinogenic process; however, two common variants were identified. The variants were not unique to tumors as 10.7% of normal individuals exhibited the variants. Nonetheless, the frequency of the variants in tumors with wild-type p53 (20.4%) was significantly greater (p = 0.05) than in normal DNAs. In contrast, the frequency of the variants (4.1%) was found to be significantly lower in tumors with p53 mutations (p = 0.006). These data suggest that the occurrence of the variants may have a direct effect on tumor development and may, in some cases, be incompatible with p53 mutations.
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PMID:Two variants of the CIP1/WAF1 gene occur together and are associated with human cancer. 765 64

Anti-PCNA monoclonal antibody and ABC staining were used to study the expressions of proliferating cell nuclear antigen/cyclin in patients with primary gallbladder carcinoma (31 cases), adenoma and tumor-like lesions of gallbladder (10 cases), and chronic cholecystitis (7 cases). The PCNA indices were 373.48 +/- 219.83, 94.9 +/- 93, and 56 +/- 28.63, respectively. This index was significantly higher in malignant lesions than in benign diseases (P < 0.01). There was a tendency that the higher the PCNA index, the lower differential degree of the gallbladder carcinoma (P < 0.01). But there were no significant correlations between the PCNA indices and the pathohistological types, the nevin classifications and the TNM classifications of the gallbladder carcinoma (P > 0.05).
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PMID:[The expressions of proliferating cell nuclear antigen (PCNA) in primary gallbladder carcinoma and its significance]. 765 96

Glucocorticoids inhibit the expression of critical cell cycle-regulatory genes. The G1 cyclin gene CcnD3, which encodes cyclin D3, is inhibited by dexamethasone in P1798 murine T lymphoma cells. Glucocorticoids also inhibit expression of the catalytic partner of cyclin D3, Cdk4. Inhibition of these two genes results in a decrease in the ability to phosphorylate the Rb-1 tumor suppressor gene product. Stable transformation with SV40 T antigen expression vectors prevents glucocorticoid-mediated cell cycle arrest, which is consistent with the conclusion that glucocorticoids inhibit Rb-1 phosphorylation. Overexpression of cyclin D3 suffices to restore Rb-kinase activity in glucocorticoid-treated cells. Nevertheless, overexpression of cyclin D3 does not prevent glucocorticoid inhibition of cell proliferation. Cells transformed with Cdk4 expression vectors, with or without cyclin D3 expression vectors, also undergo G0 arrest in the presence of dexamethasone. Glucocorticoids inhibit c-Myc expression in lymphoid cells, and transient expression of c-Myc protein attenuates the lytic response in glucocorticoid-treated human leukemia cells (R. Thulasi, D. V. Harbour, and E. B. Thompson, J. Biol. Chem., 268: 18306-16312, 1993). However, P1798 cells stably transfected with c-Myc expression vectors are sensitive to glucocorticoid-mediated G0 arrest. Such transformants withdraw from the cell cycle when treated with dexamethasone. P1798 cells were transformed so as to express both c-Myc protein and cyclin D3 in the presence of glucocorticoids. These Myc/D3 cells continue to proliferate in the presence of dexamethasone, and virtually all of these cells are capable of entering S phase in the presence of the steroid. Rapid apoptotic cell death occurs when wild-type P1798 cells are treated with dexamethasone in serum-free medium. Myc-transformed and cyclin D3-transformed cells also die rapidly when treated with glucocorticoids in the absence of serum. T antigen transformants are resistant to glucocorticoid-mediated apoptosis in serum-free medium. Double transformants that express both cyclin D3 and c-Myc are also resistant to apoptosis in the presence of dexamethasone. We conclude that inhibition of both CcnD3 and c-Myc genes is critical to glucocorticoid-mediated G0 arrest. Furthermore, those genes that convey resistance to growth arrest also convey resistance to cell death.
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PMID:c-Myc and cyclin D3 (CcnD3) genes are independent targets for glucocorticoid inhibition of lymphoid cell proliferation. 766 96

The p53 tumor-suppressor protein binds DNA and activates the expression of a 21-kDa protein that inhibits both the activity of cyclin-dependent kinases and the function of proliferating cell nuclear antigen. Since p21 expression has been reported to increase 10- to 20-fold as human diploid fibroblasts lose the ability to replicate, we examined the expression and activity of p53 during replicative aging. Similar levels of total p53 mRNA and protein were expressed in low-passage (young) and high-passage (old) cells but both DNA binding activity in vitro and transcriptional activity of p53 in vivo were increased severalfold in high-passage cells. While the basis of increased p53 activity is presently unclear, it is not correlated with differential phosphorylation or changes in p53-mouse double minute 2 gene product interactions. These results provide evidence for the activation of a protein involved in the control of cell cycle checkpoints during cellular aging, in the absence of increased expression.
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PMID:Increased activity of p53 in senescing fibroblasts. 766 93

Neoplastic diseases are characterized by uncoordinated cell growth. Cellular proliferation follows an orderly progression through the cell cycle, which is governed by protein complexes composed of cyclins and cyclin-dependent kinases. These complexes exert their regulatory function by phosphorylation of key proteins involved in cell cycle transitions, such as the product encoded by the retinoblastoma gene (pRB). Mutations and overexpression of cyclins and cyclin-dependent kinases, mainly cyclin D1 and Cdk4, have been reported and proposed to be oncogenic events. More recently, a new family of negative regulators functioning as Cdk-inhibitory molecules has been identified. Because of their recessive nature in cell cycle control and the fact that some of them are mutated in human tumors, it has been suggested that they may also function as tumor suppressor genes. It appears that the molecular networking of these proteins and complexes impact on two fundamental cell cycle regulators: p53 and pRB. Cross-talk pathways between these two nuclear proteins are being delineated, implying potential links between p53 and pRB in cell cycle control, apoptosis, and tumor progression. In addition, the high rate and mutation pattern of TP53 and RB in primary tumors have rendered them prototype tumor suppressor genes. Furthermore, detection of TP53 and RB mutations and altered expression of their encoded products appear to be of clinical significance, often correlating with prognosis, when identified in specific cancers. Based on these findings, new strategies are being developed in the emerging field of gene replacement-therapy.
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PMID:Mutations of cell cycle regulators. Biological and clinical implications for human neoplasia. 767 68

The p53 protein is a transcription regulator that is frequently altered by mutation in cancer. Breakthroughs on two fronts shed light on its role in tumor suppression. First, a flurry of biochemical and structural studies (including a partial crystal structure) has sharpened the picture of p53 topology and functional properties. Second, downstream effectors of p53 have been identified including p21Waf-1/Cip-1, an inhibitor of cyclin-dependent kinases, and bax, a dominant-negative inhibitor of bcl-2. This suggest a scenario in which p53 is activated by genotoxic stress and regulates the transcription of at least two sets of genes. One is responsible for transient cell arrest in G1 and the other controls the initiation of apoptosis. Both processes eliminate potential oncogenic mutations, either by proper DNA repair or by inducing damaged cells to commit suicide.
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PMID:The tumor suppressor protein p53: a receptor to genotoxic stress that controls cell growth and survival. 769 67

The product of the retinoblastoma gene, RB-1, is the prototype of a class of tumor suppressor genes that is expressed in most mammalian cells. The RB protein is phosphorylated in a cell cycle-dependent manner and is modulated during cellular differentiation. We have shown previously that anti-immunoglobulin M (anti-mu) treatment of WEHI-231 and CH31 B-lymphoma cells caused cell cycle blockade and apoptosis. In such arrested cells, pRB was predominantly in the underphosphorylated (active) form, in contrast to hyperphosphorylated pRB in control log phase cells. Herein we examine the modulation of pRB phosphorylation by anti-mu and its effect on a cyclin:kinase complex that can act on pRB in murine B-lymphoma cells. In unsynchronized B-lymphoma cells, anti-mu cross-linking of membrane immunoglobulin M leads to an accumulation of the hypophosphorylated form of pRB, a decrease in the abundance of one form of cyclin A, and inhibition of cyclin A and cdk2-associated kinase activity. Using centrifugal elutriation, we also show that anti-mu treatment prevents the phosphorylation of the retinoblastoma gene product only when added in early G1. In addition, there is a critical point after which membrane immunoglobulin M cross-linking is no longer effective at preventing this process. We suggest that anti-mu-mediated growth arrest is due to the direct or indirect inactivation of an active kinase complex capable of pRB phosphorylation.
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PMID:Lymphoma models for B-cell activation and tolerance: anti-immunoglobulin M treatment induces growth arrest by preventing the formation of an active kinase complex which phosphorylates retinoblastoma gene product in G1. 771 85

Abnormal expression of cell-cycle regulatory proteins, particularly cyclin D1, has been described in human cancers. However, there are few reports of this kind in experimental carcinogenesis models, which provide a framework to analyze the importance of those alterations in early cancer development. Previous studies from our laboratory showed that cyclin D1 mRNA was overexpressed in skin tumors generated in SENCAR mice by a two-stage carcinogenesis protocol. In the study presented here, immunoprecipitation of fresh tumor samples confirmed the overexpression of cyclin D1 protein. We also developed an immunohistochemical technique to determine which cells in the lesions overexpressed the cyclin and the timing of deregulation during cancer development. Surprisingly, we found that all premalignant lesions, including small incipient papillomas, overexpressed cyclin D1, whereas normal and hyperproliferative skin were negative. Nuclear immunostaining was detected only in the proliferative compartments of the tumors and showed an apparent cell-cycle-related variation. These results provide evidence for a role of cyclin D1 overexpression in mouse skin carcinogenesis and support the use of this model as an alternative to in vitro studies to help understand the involvement of cyclin deregulation in cancer development.
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PMID:Early overexpression of cyclin D1 protein in mouse skin carcinogenesis. 772 55


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