Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C1326912 (tumorigenesis)
 57,481 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human cyclin D1 has been associated with a wide variety of proliferative diseases but its biochemical role is unknown. In diploid fibroblasts we find that cyclin D1 is complexed with many other cellular proteins. Among them are protein kinase catalytic subunits CDK2, CDK4 (previously called PSK-J3), and CDK5 (also called PSSALRE). In addition, polypeptides of 21 kd and 36 kd are identified in association with cyclin D1. We show that the 36 kd protein is the proliferating cell nuclear antigen, PCNA. Cyclin D3 also associates with multiple protein kinases, p21 and PCNA. It is proposed that there exists a quaternary complex of D cyclin, CDK, PCNA, and p21 and that many combinatorial variations (cyclin D1, D3, CDK2, 4, and 5) may assemble in vivo. These findings link a human putative G1 cyclin that is associated with oncogenesis with a well-characterized DNA replication and repair factor.
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PMID:D type cyclins associate with multiple protein kinases and the DNA replication and repair factor PCNA. 135 58

Different activities of DNA viral gene products seem to be involved in the immortalization process, even in cases where continued presence of the viral genome does not seem to be required for the maintenance of the immortalized state of a cell. Immortalization, does not appear to represent a single event as implied earlier and several studies have shown that the process can be reversible. Polyomavirus large T antigen and HPV E7 (or E6 + E7) seem to possess all the activities required in vitro for immortalization of human cells, whereas one of the required activities--that defined in the two-step model as a rare mutagenic event which occurs during cellular crisis--is weaker in SV40 large T antigen and E1A. Viral functions that can activate PCNA expression (or repress Rb1 expression) have to be considered as pivotal activities in immortalization. Finally, the growth factor independence characterizing many immortalized cells could be a result of growth factor-like activities intrinsic to the viral proteins or could reflect their ability to induce autocrine growth mechanisms. These statements all relate to the first aspect of our initial hypothesis concerning cellular immortalization and in general substantiate it. Is immortalization an essential step in malignant transformation? There seems no a priori reason that transformation or tumorigenesis should depend upon cellular immortalization. Notably, many tumors appear to be mortal in culture. Growth factor independence or activation of DNA replication--essential features of immortalization--are probably of little importance for tumors in vivo where a crucial environment is supplied by the surrounding cells.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Cellular immortalization--an essential step or merely a risk factor in DNA virus-induced transformation? 228 52

Dysregulation of cyclin expression has been reported for several human malignancies, including breast cancer. To further investigate the role of cyclin genes in mammary tumorigenesis we analyzed the expression of cyclins D1, E and A and other cell cycle-related proteins in a series of nine N-methyl-N-nitrosourea-induced primary rat mammary tumors. Western blot analysis revealed a 10- to 15-fold increase in the level of cyclin D1 protein in most (7/9) of the tumors, when compared with normal rat mammary gland. The two tumors that did not show this increase also displayed negligible levels of the retinoblastoma protein. A moderate increase, 1.5- to 2-fold, in the level of cyclin E was observed in four tumors and three tumors displayed abnormal low molecular weight cyclin E-related proteins. None of the tumors showed amplification of the cyclin D1 or E genes when studied by Southern blot analysis. All nine tumors showed a 2- to 6-fold increase in the level of cyclin A protein. Most of the tumors also displayed a marked increase in levels of the CDK2 and CDK4 proteins. These changes did not appear to be simply a consequence of increased cell proliferation, as assessed by proliferating cell nuclear antigen analysis. Thus, aberrant expression of cyclins and other cyclin-related genes occurs frequently in mammary tumorigenesis in both rodents and humans.
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PMID:Deregulated expression of cyclin D1 and other cell cycle-related genes in carcinogen-induced rat mammary tumors. 755 74

Neurofibromatosis 2 (NF2), a dominantly inherited disorder, is typically manifested as bilateral vestibular Schwannomas and predisposes to other nervous system tumors. Vestibular Schwannomas also occur sporadically but the onset is usually at an older age. Surgical and histological studies have shown that vestibular Schwannomas of NF2 patients are more invasive than sporadic Schwannomas and that the two groups also have morphological differences. We compared the proliferation activity of 26 vestibular Schwannomas (19 NF2 patients) to that of 27 sporadic cases using the Ki-67 (MIB-1) and PCNA (19A2) monoclonal antibodies. In addition, proliferation was assessed in 20 spinal benign Schwannomas, 4 spinal cellular Schwannomas and 3 spinal malignant peripheral nerve sheath tumors (MPNST). We found a significant difference in the proliferation potential between NF2 and sporadic vestibular Schwannomas (MIB-1-LI: 1.72 +/- 0.93 vs 0.95 +/- 0.57, p = 0.001; and PCNA-LI: 1.40 +/- 0.75 vs 0.81 +/- 0.52, p = 0.001). Age does not explain the detected difference in proliferation, since NF2 vestibular Schwannomas also had higher MIB-1 indices than 34 age-matched sporadic tumors. In spinal tumors, MPNST had higher MIB-1 indices than cellular Schwannomas, and therefore MIB-1 staining may be useful in distinguishing between them. Although the defective NF2 gene is important in the tumorigenesis of both NF2 and sporadic Schwannomas, our results suggest that there are differences in the molecular biology of these tumors.
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PMID:Proliferative potential of sporadic and neurofibromatosis 2-associated schwannomas as studied by MIB-1 (Ki-67) and PCNA labeling. 759 50

The D-type cyclins are growth factor-regulated delayed early functions which peak at the G1/S transition, are thought to regulate entry into S phase and have been implicated in tumorigenesis. Here, we show that cyclin D2 can co-operate with Ha-Ras to impose a novel transformed state on rat embryo fibroblasts (REF). While clonal cyclin D2/Ha-Ras REF transformants exhibit a characteristic transformed phenotype in high serum, in low serum they arrest cell proliferation and display profound morphological and cytological changes indicating loss of control of cell mass and deregulation of the G1/S transition. Notably, in low serum, despite re-establishment of actin cables and arrest of proliferation, cell mass continues to increase, creating giant cells up to 10 x normal size. Also, during low-serum culture the cells make a very gradual but progressive entry into S phase, reaching a 2.4N DNA content after 6 days. PCNA is expressed and 2N and 4N cells are largely absent, and thus the cells undergo a novel S phase arrest. While transfer to low serum induced the retinoblastoma protein to enter its dephosphorylated state, and cyclin A, cyclin B and cdc2 levels to decrease, all as normal, cyclin E, cdk4, cdk2 and the exogenous cyclin D2 persisted at high levels. These results indicate that cyclin D2 and Ha-Ras can transform cells when mitogenic signals from growth factors are provided. However, in low serum, co-operation of cyclin D2 and Ha-Ras provides only a subset of the progression signals and these are sufficient for G1-related cell mass increase and S phase entry, but are insufficient for full cell cycling.
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PMID:Cyclin D2 and Ha-Ras transformed rat embryo fibroblasts exhibit a novel deregulation of cell size control and early S phase arrest in low serum. 774 96

Chronic estrogen treatment induces prolactin (PRL)-secreting pituitary tumors in laboratory animals. To determine earlier events of tumorigenesis, we studied cell proliferation in the pituitary following 7-30 days of estrogen administration in Fischer 344 rats. Immunohistochemical localization of proliferative cells by proliferating cell nuclear antigen (PCNA) staining and lactotropes by PRL staining revealed that estrogen treatment caused a time-dependent increase in the number of proliferative cells and lactotropes. Although the increase in lactotropic cell number paralleled the increase in PCNA-reactive cell number, only approximately 30% of lactotropes reacted simultaneously with the PCNA antibody. These results indicate that a subset population of lactotropes proliferates under the influence of estrogen during tumorigenesis.
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PMID:Colocalization of prolactin and proliferating cell nuclear antigen in the anterior pituitary during estrogen-induced pituitary tumors. 781 32

Because therapeutic efforts such as surgery, radiotherapy, and chemotherapy have only marginally improved the 5-year survival rate from cancers of the upper aerodigestive tract (including head and neck and lung cancers) over the past 2 decades, chemoprevention has become an important strategy in reducing the rates of incidence and mortality of these cancers. However, chemoprevention trials have been hampered by serious feasibility problems; they require large numbers of subjects and long-term follow-up for accurate determination of cancer incidence and they are very costly. Because the use of intermediate end points would reduce the duration and costs of these studies, biomarkers that could serve as such end points have recently become a subject of great interest. With the strengthening of the assumption that tumorigenesis is a multistep process of transformation from normal tissues to malignant lesions, there has been a great effort to examine each of these steps for genetic and/or phenotypic alterations that might be candidates for such biomarkers. These candidates include genomic markers, certain specific gene alterations, such as tumor suppressor genes, oncogenes, growth factors and their receptors, proliferation markers, and differentiation markers. In this review, we describe several genomic markers, including micronuclei, chromosomal alterations, and specific genetic markers, e.g., the ras gene family, erb B1, int-2/hst-1, and p53 tumor suppressor gene. We also review the proliferation markers, including proliferating cell nuclear antigen, and squamous cell differentiation markers, including keratins, involucrin, and transglutaminase 1. These biomarker candidates have the potential to be important adjuncts to the development of new chemopreventive agents and to the rational design of future intervention trials. However, we can not overemphasize that these markers need to be validated in clinical trials; only then can they replace cancer incidence as the sole end point for chemoprevention trials.
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PMID:Biomarkers in upper aerodigestive tract tumorigenesis: a review. 788 44

Application of ionizing radiation to adult rat major salivary glands tested tenets of the bicellular reserve cell hypothesis for the induction of salivary gland tumors, namely, that stem cells preferentially located to luminal cells of the intercalated duct and basal cells of the excretory duct in normal salivary glands. The effect of a single, low dose (3000 cGy) of x-radiation administered to the parotid and submandibular glands was followed with the use of immunocytochemistry and an antibody to the cell cycle-related protein proliferating cell nuclear antigen to detect the kinetics and localization of cycling cells up to 15 days postirradiation. Maximal responses occurred in acinar cells (12.6-fold increase) of submandibular glands on day 7 postirradiation. Similar but less dramatic concurrent increases in proliferating cells were evident in intercalated (3.4-fold) and striated (2.2-fold) duct cells, but little response was seen in basal or luminal cells of submandibular gland excretory ducts. A limited but maximal proliferative response again occurred on day 7 in the parotid gland. Neither in the steady state nor irradiated submandibular gland was there evidence of specific stem ("reserve") cells associated with the intercalated or excretory ducts. It appears unnecessary to invoke stem cells in a model of cellular proliferation in salivary glands. Therefore current concepts of salivary gland tumorigenesis require modification because all cell types, including acinar cells, are at risk in the carcinogenic process.
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PMID:The pathobiology of salivary gland. III. PCNA-localization of cycling cells induced in rat submandibular gland by low-dose x-radiation. 790 8

Bile acids are reported to enhance experimentally-induced colonic tumorigenesis. Previously we have reported that cholic acid, a known tumor promoter, actually reduced the number of aberrant crypt foci (ACF), purported preneoplastic lesions (B.A. Magnuson and R.P. Bird, Cancer Lett., 68 (1993), 15-23). This observation was unexpected and has prompted us to explore the effect of other bile acids on the development of ACF. The primary objective of this investigation was to evaluate the effect of feeding varying dosages of chenodeoxycholic acid (CDC) on the induction and growth of ACF and on the proliferative indices of the colonic epithelium. Sprague-Dawley male rats were injected with azoxymethane (+AOM, 20 mg/kg) or saline (-AOM). One week later they were randomly allocated to five groups and were fed diets containing CDC at varying levels (0.0, 0.025, 0.05, 0.1 and 0.2% by weight) for 2 weeks. After completion of the feeding period the number and crypt multiplicity of ACF were quantified, and three different proliferative indices, including mitotic index, BUDR labelling index (percentage S-phase cells) and proliferating cell nuclear antigen labelling index (percentage cycling cells) were determined. CDC at all dosages increased the number of ACF having the maximum effect at the 0.1% CDC level. A significant dose-related increase in crypt height was noted in CDC-fed+AOM groups when compared with the +AOM control groups. The mitotic indices of colonic crypts were higher (P < or = 0.05) only in the 0.025% CDC -AOM group when compared with the 0% CDC -AOM group (5.97 +/- 0.63 vs. 3.92 +/- 0.79). The BUDR labelling indices were not altered by CDC feeding (P > or = 0.05). PCNA labelling indices increased consistently among the CDC-fed groups. Among the -AOM group the 0.05% CDC group had the maximum value, which was significantly different from the control value (19.21 +/- 1.92 vs. 10.93 +/- 0.56, respectively). Among the +AOM groups the PCNA labelling indices increased with increasing levels of CDC. It was concluded that CDC stimulated the development of ACF and altered cell cycle associated events in colonic crypts undergoing neoplastic changes.
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PMID:The effect of chenodeoxycholic acid on the development of aberrant crypt foci in the rat colon. 790 6

We studied the expression of p21, the ras encoded protein, in primary tumour of 45 patients with papillary thyroid cancer (PTC). Patients were grouped according to outcome so that one group (31 patients) had a good outcome and the other (14 patients) a fatal outcome, after a follow-up of at least 5 years. The presence of p21 ras protein was assessed by immunohistochemistry with a specific monoclonal antibody (MAb Y-13259). The results were correlated with the outcome, with the expression of proliferating cell nuclear antigen (PCNA)/cyclin (as a marker of cell proliferation) and with other well established prognostic factors for PTC (age, grading, extension and tumour size; Endocrinol Metab Clin North Am 1990, 19, 545-576). p21 staining in tumours of living patients was negative in 15, weakly positive (1+) in 10 and strongly positive (2+ or more) in 6 patients. In tumours from deceased patients, p21 staining was negative in 1, weakly positive in 2 and strongly positive in the remaining 11 patients (P < 0.001, chi 2). PCNA immunostaining was increased in 63.6% (7/11) of the tumours from deceased patients compared to 17.8% (5/28) of the tumours of living patients, but no direct correlation was found between p21 and PCNA expression. Among the other prognostic factors studied, only age > or = 40 years was a significant predictor of poor outcome. The survival curve of patients with strongly positive p21 staining was similar to that of patients aged > or = 40 years at the time of diagnosis. The combination of p21 > or = 2+ and age > or = 40 was superior to age alone (P < 0.05) as a prognostic indicator of poor outcome. In conclusion, our results indicate that the p21 product of the ras (proto)oncogene is differently expressed in PTC, in relation to the degree of aggressiveness. Regardless of the pathogenetic role of the ras oncogene in thyroid tumorigenesis, our data indicate that the expression of the p21 ras protein may be regarded as a prognostic indicator in PTC. Furthermore, overexpression of p21 ras protein is associated with patients in the older age groups, and might contribute to the poor prognosis of elderly patients.
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PMID:Expression of p21 ras protein as a prognostic factor in papillary thyroid cancer. 790 18


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