Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The retinoids are reported to reduce second primary aerodigestive tract tumors in patients with prior lung or head and neck carcinomas. Yet, the optimal retinoid useful for chemoprevention and those mechanisms linked to this chemoprevention are not identified. This study reports an in vitro model for carcinogen-induced transformation of immortalized human bronchial epithelial (BEAS-2B) cells that was adapted to study the anti-carcinogenic effects of all-trans-retinoic acid (RA). Following exposure to carcinogens: cigarette smoke condensate (CSC) or N-nitrosamine-4-(methylnitrosamino)-1-(3 pyridyl)-1-butanone (NNK), BEAS-2B cells exhibited evidence of transformation. This included an increased anchorage independent growth or acquired ability to form tumors in athymic mice. This transformation was inhibited by RA as demonstrated by a lack of augmented anchorage independent growth or tumor formation in athymic mice for the cells treated with RA. The BEAS-2B cells transformed by NNK exhibited an increase in cyclin E expression which was associated with an increase in the cyclin E-Cdk2 kinase activity. Over-expression of human cyclin E by transfection shows cyclin E enhances the basal clonal growth of BEAS-2B cells. In both the parental and transformed BEAS-2B cells, RA down-regulated cyclin E protein levels which was associated with an inhibition of growth and an accumulation of cells in G1. The data reported here suggest the decline of cyclin E expression represents a potential mechanism for the RA-induced growth suppression which is linked to the anti-carcinogenic effects of RA. Thus, this study reports the adaption of an in vitro model of lung carcinogenesis suitable to test the activity of chemoprevention agents.
 ...
PMID:Inhibited transformation of immortalized human bronchial epithelial cells by retinoic acid is linked to cyclin E down-regulation. 893 45

Inhibitors of cyclin-dependent kinases provide a major mechanism of negative regulation on cell cycle progression. Defects in the function of the CDK inhibitors may lead to uncontrolled cell proliferation and potentially facilitate tumorigenesis. The p16INK4 family of CDK inhibitors specifically prevent the phosphorylation of the retinoblastoma susceptibility gene product, pRb, by inhibiting the kinase activity of CDK4 and CDK6, thereby keeping pRb in its active form as a growth suppressor. The loss of p16INK4 inhibitory activity would, therefore, have the same consequence as the loss of pRb growth suppressing activity. The p16INK4 family currently includes four members, p15INK4b, pl6INK4a, pl8INK4c and p19INK4d. Two members, p15INK4b and pl6INK4a have been found to be deleted and mutated in a variety of human tumor-derived cell lines and primary tumors. In the present study we have examined the genomic status of the newly isolated p19INK4d gene in 75 tumor-derived cell lines; 13 immortalized, transformed or normal cell lines; 19 ovarian tumors and 18 acute myelogenous leukemias. No deletions or point mutations were observed in the pl9INK4d gene. A genetic polymorphism at codon 30 (CGC-->CGG) in exon 1 of the pl9INK4d gene was observed in 10% of the samples under investigation. In the same set of samples, p16INK4a was found to be homozygously deleted in 32% of the tumor derived cell lines. These results together with our previous data that showed a 22% deletion frequency in p15INK4b and rare alterations in the pl8INK4c gene, indicating that the p16INK4a and pl5INK4b, but not the p18INK4c and pl9INK4d genes, are frequently mutated in human tumors. Hence, members of the p16INK4 CDK inhibitor family, while evolutionary related and biochemically indistinguishable, carry out distinct biological functions.
 ...
PMID:Lack of mutation in the cyclin-dependent kinase inhibitor, p19INK4d, in tumor-derived cell lines and primary tumors. 893 52

Normal somatic cells of higher organisms do not divide indefinitely. After a finite number of divisions, normal cells irreversibly cease proliferation by a process termed replicative or cellular senescence. Replicative senescence is controlled by multiple, dominant-acting genes about which very little is known. The only genes known to reactivate DNA synthesis in senescent cells are viral oncogenes encoding proteins that bind and inactivate the p53 and retinoblastoma (pRb) tumor suppressor proteins. SV40 T antigen is the best studied of these viral oncoproteins. T[K1] is a T antigen point mutant that selectively is defective in binding pRb and the pRb-related proteins p107 and p130. We show that T[K1] stimulated quiescent human fibroblasts to synthesize DNA nearly as well as wild-type T but was incapable of stimulating senescent cells. We tested several growth regulatory genes that are repressed in senescent cells for ability to restore activity to T[K1]. These included c-fos, c-jun, Id-1, Id-2, E2F-1, and cdc2. Only the helix-loop-helix (HLH) protein, Id-1, restored the ability of T[K1] to reactivate DNA synthesis in senescent cells. This activity of Id-1 was not shared by Id-2, a related protein, and depended on an intact HLH domain. It did not appear that Id-1 interacted directly with pRb or p107. Constitutive Id-1 expression failed to rescue proliferating cells from growth inhibition by pRb, p107, or p130, and failed to interact with pRb in the yeast two hybrid system. Because Id proteins negatively regulate basic-HLH (bHLH) transcription factors, we suggest that senescent cells express one or more bHLH factor that cooperates with pRb, or pRb-related proteins, to suppress proliferation.
 ...
PMID:The helix-loop-helix protein Id-1 and a retinoblastoma protein binding mutant of SV40 T antigen synergize to reactivate DNA synthesis in senescent human fibroblasts. 893 78

Progression through the cell cycle is dependent on the sequential expression of cyclins, which combine with cyclin-dependent kinases (cdks) to form active kinases. The transition from G1 to S phase is dependent on D cyclins in complex with cdk4 or cdk6 and cyclin E complexed with cdk2. One target of G1 cyclins is the retinoblastoma susceptibility protein (Rb). Rb is a transcriptional repressor that is selectively targeted to genes through interaction with the E2F family of cell cycle transcription factors. Rb is a member of a family of proteins that include p107 and p130. The three proteins share a region known as the pocket that is important for binding E2F and is also the binding site for oncoproteins from DNA tumor viruses that inactivate Rb. We have found that two conserved domains within the Rb pocket (A and B) interact to form a transcriptional repressor motif (K. N. B. Chow and D. C. Dean, Mol. Cell. Biol. 16:4862-4868, 1996). Here we demonstrate that p107 also has an A-B repressor motif, and using domain swapping and coimmunoprecipitation assays, we compare A and B from Rb and p107. Finally and most importantly, we demonstrate that the A-B interaction which forms the repressor motif is blocked by G1 cdk phosphorylation, thereby blocking repressor activity. This A-B repressor motif is then the first example of a cdk-regulated transcriptional repressor.
 ...
PMID:The Rb family contains a conserved cyclin-dependent-kinase-regulated transcriptional repressor motif. 894 73

Selenium, both organic and inorganic forms, inhibit mammary tumorigenesis in vivo and mammary cell growth in vitro. In the present study, sodium selenite was compared to methylselenocysteine (MSC) for their individual effects on cell growth, cdc2/cdk2 kinase activities and the levels of cyclins D1, E and A bound to cdk2 in a mouse mammary epithelial cell culture model. Selenite arrested the growth of cells in S-G2-M phase in contrast to MSC which arrested or delayed the cells in G1. In MSC-treated cells there was a 57% drop in the cdk2 kinase activity accompanied by a 73.5% decrease in cyclin E-cdk2 content as compared to the control cells. Selenite treatment increased the cdk2 kinase activity by 30% without any appreciable change in either of the cyclins D1, E or A bound to cdk2 when compared to the control cells. These data support the hypothesis that selenite and MSC have distinct modes of action in the inhibition of cell growth in vitro. Selenite has a strong genotoxic effect on the tumor cells; in contrast, MSC appears to inhibit cell growth via specific inhibition of cell cycle regulatory proteins.
 ...
PMID:Organic and inorganic selenium compounds inhibit mouse mammary cell growth in vitro by different cellular pathways. 894 25

Deregulated expression of several cell cycle regulatory genes has been demonstrated to be associated with cancer. In particular, a strong correlation has been established between inappropriate cyclin E expression and human breast cancer. To determine the ability of cyclin E to play a causative role in mammary tumorigenesis, regulatory sequences from the ovine beta-lactoglobulin gene were utilized to specifically target expression of human cyclin E to the mammary glands of pregnant and lactating mice. Lactating mammary glands of transgenic mice expressing cyclin E contained areas of hyperplasia, primarily papillary projections of hyperplastic cells, which were rarely observed in lactating glands of control mice. Over 10% of female cyclin E transgenic mice have developed mammary carcinomas, with latencies ranging from 8 to 13 months. Tumor analysis revealed the presence of transgene-specific cyclin E RNA and protein, as well as cyclin E- and cdk2-associated kinase activity, suggesting that cyclin E is likely a contributing component of tumorigenic progression in this model system.
 ...
PMID:Induction of mammary gland hyperplasia and carcinomas in transgenic mice expressing human cyclin E. 897 26

We report the isolation of a large cyclophilin protein containing RS (arginine-serine) repeats from a yeast two-hybrid screen using ClK (CDC28/cdc2-like kinase) as a probe. This Clk associating RS-cyclophilin (CARS-Cyp) possesses 39% homology to the NK-TR1 (natural killer tumor recognition protein-1) we have previously characterized (Anderson et al. (1993) Proc. Natl. Acad. Sci. USA 90 (1993) 542-546). CARS-Cyp is expressed in a variety of tissues and cell types, and codes for a protein with a predicted mass of 89 kDa containing a cyclophilin-related domain, two Nopp140 (nucleolar phosphoprotein of 140 kDa)-related domains, and a large RS domain. The RS-cyclophilins, a novel class of proteins, may play an important role in the regulation of pre-mRNA splicing.
 ...
PMID:RS cyclophilins: identification of an NK-TR1-related cyclophilin. 897 60

Cyclin E is an important regulator of cell cycle progression that together with cyclin-dependent kinase (cdk) 2 is crucial for the G1/S transition during the mammalian cell cycle. Previously, we showed that severe overexpression of cyclin E protein in tumor cells and tissues results in the appearance of lower molecular weight isoforms of cyclin E, which together with cdk2 can form a kinase complex active throughout the cell cycle. In this study, we report that one of the substrates of this constitutively active cyclin E/cdk2 complex is retinoblastoma susceptibility gene product (pRb) in populations of breast cancer cells and tissues that also overexpress p16. In these tumor cells and tissues, we show that the expression of p16 and pRb is not mutually exclusive. Overexpression of p16 in these cells results in sequestering of cdk4 and cdk6, rendering cyclin D1/cdk complexes inactive. However, pRb appears to be phosphorylated throughout the cell cycle following an initial lag, revealing a time course similar to phosphorylation of glutathione S-transferase retinoblastoma by cyclin E immunoprecipitates prepared from these synchronized cells. Hence, cyclin E kinase complexes can function redundantly and replace the loss of cyclin D-dependent kinase complexes that functionally inactivate pRb. In addition, the constitutively overexpressed cyclin E is also the predominant cyclin found in p107/E2F complexes throughout the tumor, but not the normal, cell cycle. These observations suggest that overexpression of cyclin E in tumor cells, which also overexpress p16, can bypass the cyclin D/cdk4-cdk6/p16/pRb feedback loop, providing yet another mechanism by which tumors can gain a growth advantage.
 ...
PMID:Cyclin E, a redundant cyclin in breast cancer. 898 90

We investigated the in vivo expression of cyclin B1 and Cdc2 (key molecules for G2-M transition during the cell cycle) in nonmalignant and cancerous human breast lesions using immunohistochemistry and quantitative proliferative index (PI) analysis. Breast epithelial cells co-expressed cyclin B1 and Cdc2 in their cytoplasm in the G2 phase and in their nuclei in the M phase. Cyclin B1, but not Cdc2, immunostaining rapidly disappeared from the nuclei during the mitotic metaphase to anaphase transition. Static image analysis revealed the mean proliferative index for cyclin B1/cdc2 for each type of lesion to be as follows: normal glands (n = 20), 2.0/2.5%; benign lesions, including typical ductal hyperplasia (n = 76), 2.5/5.8%; atypical ductal hyperplasia (n = 21), 3.0/6.6%; carcinomas in situ (n = 70), 7.4/14.0%; and invasive carcinomas (n = 58), 10.0/22.9%. Proliferative index data for atypical hyperplasia were virtually identical to those for benign lesions and were significantly lower than those for breast cancer, suggesting that expression levels of cyclin B1 and Cdc2 may be used to distinguish premalignant human breast lesions from advanced disease. Furthermore, the proliferative index for cyclin B1 for comedo-type ductal carcinomas in situ agreed with that for invasive ductal carcinomas (mean, 10.1% versus 9.5%), apparently explaining the clinicopathological aggressiveness of this tumor at the molecular level.
 ...
PMID:Expression of the G2-M checkpoint regulators cyclin B1 and cdc2 in nonmalignant and malignant human breast lesions: immunocytochemical and quantitative image analyses. 900 17

Deletion at 9p21 is frequent in many tumor types. A candidate tumor suppressor gene, p16INK4a, was mapped to this region and is frequently inactivated by several different mechanisms in many tumor types, including non-small cell lung cancer, but not in small cell lung cancer (SCLC). p16 functions as a cyclin/CDK inhibitor to prevent phosphorylation of pRB. It has been demonstrated that most SCLCs have lost pRB but retained p16, and the inactivation of pRB excludes the inactivation of p16 and vice versa. To determine the potential existence of other tumor suppressor genes on the short arm of chromosome 9 in SCLC, we tested 46 primary SCLCs by microsatellite analysis. We found that more than 89% of the tumors exhibited loss of heterozygosity (LOH) at 9p with three distinct minimal deleted areas. Among those areas, LOH at 9p21 was most frequent (86%), with a peak at a marker 150 kb telomeric to p16INK4a. LOH was also observed in more than 50% of the tumors at two other regions, 9p22 and 9p13. Our data strongly suggest the presence of at least three novel tumor suppressor loci on 9p in SCLC, and further investigations to clone candidate tumor suppressor genes are warranted.
 ...
PMID:Identification of three distinct tumor suppressor loci on the short arm of chromosome 9 in small cell lung cancer. 901 64


<< Previous 1 2 3 4 5 6 7 8 9 10