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)

Telomerase is a ribonucleoprotein enzyme that adds hexanucleotide repeats TTAGGG to the ends of chromosomes. Telomerase activation is known to play a crucial role in cell-immortalization and carcinogenesis. Telomerase is shown to have a correlation with cell cycle progression, which is controlled by the regulation of cyclins, cyclin dependent kinases (cdks) and cyclin dependent kinase inhibitors (cdkis). Abnormal expression of these regulatory molecules may cause alterations in cell cycle with uncontrolled cell growth, a universal feature of neoplasia. Skin cancer is the most prevalent form of cancer in humans and the solar UV radiation is its major cause. Here, we investigated modulation in telomerase activity and protein expression of cell cycle regulatory molecules during the development of UVB-induced tumors in SKH-1 hairless mice. The mice were exposed to 180 mjoules/cm2 UVB radiation, thrice weekly for 24 weeks. The animals were sacrificed at 4 week intervals and the studies were performed in epidermis. Telomerase activity was barely detectable in the epidermis of non-irradiated mouse. UVB exposure resulted in a progressive increase in telomerase activity starting from the 4th week of exposure. The increased telomerase activity either persisted or further increased with the increased exposure. In papillomas and carcinomas the enzyme activity was comparable and was 45-fold higher than in the epidermis of control mice. Western blot analysis showed an upregulation in the protein expression of cyclin D1 and cyclin E and their regulatory subunits cdk4 and cdk2 during the course of UVB exposure and in papillomas and carcinomas. The protein expression of cdk6 and ckis viz. p16/Ink4A, p21/Waf1 and p27/Kip1 did not show any significant change in UVB exposed skin, but significant upregulation was observed both in papillomas and carcinomas. The results suggest that telomerase activation may be involved in UVB-induced tumorigenesis in mouse skin and that increased telomerase activity may be associated with G1 phase of the cell cycle.
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PMID:Activation of telomerase and its association with G1-phase of the cell cycle during UVB-induced skin tumorigenesis in SKH-1 hairless mouse. 1002 11

Mitogenic and growth inhibitory signals influence the activity of a family of cyclin dependent kinases (cdks). p27 is an important cdk inhibitor, acting in G1 to inhibit cyclin-cdks. As negative growth regulators, the cdk inhibitors may function as tumor suppressors. While the p16 gene plays a tumor suppressor role in cancers, p27 gene mutations have been identified only rarely. While high levels of p27 protein are expressed in normal human mammary epithelium, loss of p27 is frequent and is of independent prognostic significance in breast cancers. Low p27 is also a poor prognostic factor in colon, gastric, esophageal, lung, and prostate carcinomas, and enhanced proteasomal degradation may underlie loss of p27 in tumor cells. Loss of p27 has not been significantly correlated with tumor proliferation in a number of studies and may reflect alterations in differentiation and adhesion-dependent growth regulation germane to oncogenesis and tumor progression. Efforts to confirm the prognostic value of p27 are under way in a number of large breast cancer studies. These studies may also indicate whether loss of p27 in association with other traditional or novel markers has greater prognostic potential than each factor alone. p27 immunostaining is inexpensive and reliable and may become part of the routine histopathologic processing of tumors in the near future. Widespread application of p27 in prognostic testing will require greater uniformity in scoring techniques and determination of the cut off levels which distinguish individuals at high and low risk of cancer recurrence and death. Finally, the greatest utility of p27 may lie in the information it sheds on the biology of aberrant growth regulation in breast cancer and the potential to use this in the generation of novel therapeutic strategies.
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PMID:Prognostic implications of expression of the cell cycle inhibitor protein p27Kip1. 1006 70

The geranylgeranyltransferase I inhibitor GGTI-298 has recently been shown to arrest human tumor cells in the G1 phase of the cell cycle, induce apoptosis, and inhibit tumor growth in nude mice. In the present manuscript, we provide a possible mechanism by which GGTI-298 mediates its tumor growth arrest. Treatment of the human lung carcinoma cell line Calu-1 with GGTI-298 results in inhibition of the phosphorylation of retinoblastoma protein, a critical step for G1/S transition. The kinase activities of two G1/S cyclin-dependent kinases, CDK2 and CDK4, are inhibited in Calu-1 cells treated with GGTI-298. Furthermore, GGTI-298 has little effect on the expression levels of CDK2, CDK4, CDK6, cyclins D1 and E, but decreases the levels of cyclin A. GGTI-298 increases the levels of the cyclin-dependent kinase inhibitors p21 and p15 and had little effect on those of p27 and p16. Most interesting is the ability of GGTI-298 to induce partner switching for several CDK inhibitors. GGTI-298 promotes binding of p21 and p27 to CDK2 while decreasing their binding to CDK6. Reversal of partner switching and G1 block was observed after removal of GGTI-298. Furthermore, GGTI-298 treatment results in an increased binding of p15 to CDK4, which is paralleled with decreased binding to p27. The results demonstrate that the GGTI-298-mediated G1 block in Calu-1 cells involves increased expression and partner switching of CDK inhibitors resulting in inhibition of CDK2 and CDK4, and retinoblastoma protein phosphorylation.
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PMID:The geranylgeranyltransferase I inhibitor GGTI-298 induces hypophosphorylation of retinoblastoma and partner switching of cyclin-dependent kinase inhibitors. A potential mechanism for GGTI-298 antitumor activity. 1006 46

Progression through the cell cycle is governed by cyclin-dependent kinases (cdks), whose activity is inhibited by the cdk inhibitors. Cyclins, cdks, and cdk inhibitors are frequently deregulated in cancers. This chapter reviews the prognostic significance of alterations in cdk inhibitors. Loss of p27 protein provides independent prognostic information in breast, prostate, colon, and gastric carcinomas, and immunohistochemical (IHC) staining for p27 may eventually become part of routine histopathologic processing of cancers. Loss of IHC staining for p21 may be prognostic in certain cancers but conflicting results are reported in breast cancer. Reports on homozygous deletion of p16 and p15 genes suggest the value of larger, prospective studies with standardized treatment protocols to definitively establish the prognostic utility of p15/p16 deletions in acute leukemias. Larger trials and the development of a consensus on methods for deletion analysis, IHC staining, and tumor scoring will be needed to move these molecular assays from bench to bedside.
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PMID:The prognostic significance of altered cyclin-dependent kinase inhibitors in human cancer. 1007 86

To elucidate the mechanism of tumor extension in human pulmonary adenocarcinoma, we immunohistochemically investigated the expression of cell cycle regulator proteins in 54 small adenocarcinomas less than 3 cm in diameter. The Ki-67-labeling index was significantly higher in the periphery of the tumor nodule than in the center. This proliferative potential correlated well with coexpression of cdk2 and cyclin A. p27, one of the cdk inhibitors, was highly expressed in normal bronchial epithelial cells. Peripherally located tumor cells expressed p27 at an intermediate level, but at a higher frequency and level than those in the center. Expression of p21 was also predominant in the periphery. Furthermore, the expression patterns of p21 and p27 were reciprocal. In vitro kinase assays further demonstrated higher cdk2 kinase activity in the periphery. These results suggest that: (i) within an emerging extension made up of peripherally located tumor cells, their high proliferative potential gradually wanes as their relative topographical position becomes more central in the expanding tumor; (ii) peripherally located tumor cells maintain their proliferative potential by higher cyclin A-cdk2 complex activity; and (iii) intermediate expression of p21/p27 in the peripherally located cells promotes higher cyclin A-cdk2 kinase activity, whereas high p21/p27 expression in nonneoplastic cells inhibits kinase activity.
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PMID:Tumor extension and cell proliferation in adenocarcinomas of the lung. 1007 69

Classical cytotoxic therapy has been minimally useful in the treatment of hepatocellular carcinoma. In an effort to develop a new approach to the treatment of this neoplasm, we have investigated the signal transduction pathways regulating the growth of human hepatoma cells. In the data reported here, cyclic AMP (cAMP), a negative growth regulator for many cells of epithelial origin, induced G1 synchronization and apoptosis in the HepG2 human hepatoma cell line. The effects of cAMP on the components of the G1/S transition were analyzed. There was no detectable effect of two different cAMP analogs, 8-bromo cAMP or dibutyryl cAMP on the level of the D-type cyclins, cyclin E, cyclin-dependent kinase 2, cyclin-dependent kinase 4, p53, or the cyclin-dependent kinase inhibitors p21 or p27. In contrast, the cAMP analogs induced a dramatic downregulation of cyclin A protein, cyclin A messenger RNA, and cyclin A-dependent kinase activity. Cyclin A-dependent kinase has been shown to be required for the G1-S transition. Furthermore, cyclin A deregulation has been implicated in the pathogenesis of hepatocellular carcinoma. The data reported here suggest a novel signal transduction-based approach to hepatoma therapy.
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PMID:Cyclic AMP induces inhibition of cyclin A expression and growth arrest in human hepatoma cells. 1020 5

The molecular mechanisms leading to increased cellular proliferation rates and, thus, tumor formation in the anterior pituitary gland are poorly understood. The cyclin-dependent kinase inhibitor p27Kip1 is a key molecule regulating the G1 phase of the cell cycle in many cell types. Furthermore, it was shown that p27 knock-out mice develop pro-opiomelanocortin-positive pituitary tumors. In an effort to clarify the role of p27 in the normal and tumorous human pituitary, we studied the expression of p27 by immunohistochemistry, using a highly specific mouse monoclonal anti-human p27 antibody. Normal pituitaries and 54 pituitary adenomas (twelve somatotrope adenomas, nine prolactinomas, twelve corticotrope adenomas, three TSH-producing tumors, six gonadotrope adenomas, six null cell adenomas, and six oncocytomas) were analyzed. p27 expression was determined semiquantitatively with regard to both the percentage of positive cells and the intensity of the staining. Normal human pituitaries showed strong expression of p27 in most nuclei. In contrast, the levels of p27 were reduced in the majority of the tumors analyzed. Twenty-two tumors (six somatotrope adenomas, five prolactinomas, four corticotrope adenomas, two TSH-producing tumors, two gonadotrope adenomas, and three null cell adenomas) were completely p27-negative. In 18 tumors, p27 expression was found in < or = 10% of the cells. In the other ten tumors, 11-80% of the cells were p27-positive. In summary, we were able to demonstrate reduced expression levels of the cell-cycle inhibitor p27 in tumors derived from all pituitary cell types. Our data indicate that p27 may be an important regulator of cellular proliferation in the anterior pituitary, the underexpression of which could play a role in pituitary tumorigenesis.
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PMID:Reduced expression levels of the cell-cycle inhibitor p27Kip1 in human pituitary adenomas. 1021 21

Multicellular contact has been shown to influence the in vitro sensitivity of cells to drug treatment. We investigated the use of macroporous gelatin microcarriers, CultiSpher-G, as a convenient laboratory system for the molecular analysis of this "contact effect". We determined that human A549 cells can be grown in CultiSphers with growth and cell cycle parameters similar to those of monolayers. In addition, cells in CultiSphers express less p27/kip1, an indicator of cell cycle arrest, than equivalent cells in monolayers. When treated with drugs, A549 cells grown in CultiSphers or monolayers accumulate equivalent amounts of platinum-DNA adducts and similar amounts of doxorubicin. Moreover, A549 and KB-3-1 cells in CultiSphers have significantly decreased sensitivity to cis-platinum(II)diammine dichloride (cisplatin), 4-hydroperoxycyclophosphamide, doxorubicin, and paclitaxel (taxol) compared with cells in monolayers when assayed by clonogenic survival. Cisplatin treatment in monolayers or CultiSphers did not result in apoptotic cell death. In contrast, paclitaxel caused a significant amount of sub-G1 DNA, an indicator of apoptosis, which was diminished when cells were grown in CultiSphers compared with monolayers. When grown in CultiSphers, cells with abrogated p53 function (A549/16E6 and NCI-H1299) were less sensitive to cisplatin than the corresponding monolayer cells, indicating that the decrease in sensitivity is p53 independent. Taken together, the data suggest that CultiSpher-G microcarriers are a useful in vitro system to examine the effects of three-dimensional cell contact on drug sensitivity of human tumor cells.
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PMID:Growth of human tumor cells in macroporous microcarriers results in p53-independent, decreased cisplatin sensitivity relative to monolayers. 1022 May 73

p27/kip-1 is a 'universal inhibitor' which inhibits cyclin complexes with cyclin-dependent kinases (CDKs), preventing cell cycle from the G1-S progression. It is expressed in normal oligodendrocytes and in differentiated glial tumors, decreasing with anaplasia and malignancy. In non-astrocytic and non-oligodendrocytic tumors of the nervous system, such as meningiomas, schwannomas, medulloblastomas, neuroblastomas and malignant lymphomas, p27/kip-1 is inconstantly and sometimes poorly expressed. This can be due to the lacking of p27 expression in the normal counterpart of tumor cells. In some tumors, p27/kip-1 expression can be attributed to a differentiation process, as in the pale islands of desmoplastic medulloblastoma and in neuroblastomas. A correlation of p27/kip-1 expression with histology was not found, with the exception of apoptosis in medulloblastomas. p27/kip-1 is in feed-back with cyclins and CDKs for the control of cell proliferation and its expression may occur where requested by the interplay with cyclins and other inhibitors.
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PMID:Cell-cycle inhibitor p27/Kip-1 expression in non-astrocytic and non-oligodendrocytic human nervous system tumors. 1032 6

Mammalian cell-cycle progression is regulated by the combined action of cyclins/cyclin-dependent kinases (cdks) and cdk inhibitors. Abnormal expression as well as interaction of these proteins may result in malignant transformation of cells. To further address alterations and roles of these cell-cycle proteins in the development of epithelial ovarian carcinomas, we analyzed the expression of the p27(kip1), cyclin D1, cyclin E, and cdk2. A panel of 79 epithelial ovarian tumors was selected. Immunohistochemical staining of serial paraffin sections was performed using antibodies to p27(kip1), cyclin D1, cyclin E, and cdk2. The results showed that p27(kip1) and cyclin D1 were concurrently expressed in epithelial ovarian tumors, and the expression was down-regulated in ovarian carcinomas. There was an inverse relationship between the expression level of p27(kip1) and cyclin D1 and the histological tumor grades. On the other hand, the expression of cyclin E and cdk2 was enhanced in ovarian carcinomas. The results suggest that low expression of p27(kip1) and cyclin D1 as well as high expression of cyclin E and cdk2 promotes the development of ovarian tumors. p27(kip1) and cyclin D1 expression are negatively correlated with the malignant degree of epithelial ovarian tumors. Thus, the ovarian tumors with high p27(kip1) and cyclin D1 expression may generally have a somewhat better prognosis, while those with low p27(kip1) and cyclin D1 expression may have a worse prognosis.
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PMID:The concurrent expression of p27(kip1) and cyclin D1 in epithelial ovarian tumors. 1032 35


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