Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Members of the INK4 protein family specifically inhibit cyclin-dependent kinase 4 (cdk4) and cdk6-mediated phosphorylation of the retinoblastoma susceptibility gene product (Rb). p16INK4A, a prototypic INK4 protein, has been identified as a tumor suppressor in many human cancers. Inactivation of p16INK4A in tumors expressing wild-type Rb is thought to be required in order for many malignant cell types to enter S phase efficiently or to escape senescence. Here, we demonstrate another mechanism of tumor suppression by implicating p16INK4A in a G1 arrest checkpoint in response to DNA damage. Calu-1 non-small cell lung cancer cells, which retain Rb and lack p53, do not arrest in G1 following DNA damage. However, engineered expression of p16INK4A at levels compatible with cell proliferation restores a G1 arrest checkpoint in response to treatment with gamma-irradiation, topoisomerase I and II inhibitors, and cisplatin. A similar checkpoint can be demonstrated in p53-/- fibroblasts that express p16INK4A. DNA damage-induced G1 arrest, which requires the expression of pocket proteins such as Rb, can be abrogated by overexpression of cdk4, kinase-inactive cdk4 variants capable of sequestering p16INK4A, or a cdk4 variant incapable of binding p16INK4A. After exposure to DNA-damaging agents, there was no change either in overall levels of p16INK4A or in amounts of p16INK4A found in complex with cdks 4 and 6. Nonetheless, p16INK4A expression is required for the reduction in cdk4- and cdk6-mediated Rb kinase activity observed in response to DNA damage. During tumor progression, loss of p16INK4A expression may be necessary for cells with wild-type Rb to bypass this G1 arrest checkpoint and attain a fully transformed phenotype.
Mol Cell Biol 1998 Jan
PMID:p16INK4A participates in a G1 arrest checkpoint in response to DNA damage. 941 85

The fibroblast growth factor (FGF) receptor complex is a ubiquitous regulator of development and adult tissue homeostasis that bridges the peri-cellular matrix and the intracellular environment. Diverse members of the FGF polypeptide family, the FGF receptor tyrosine kinase (FGFRTK) family and the FGF receptor heparan sulfate proteoglycan (FGFRHS) family combine to result in active and specific FGFR signal transduction complexes. Regulated alternate splicing and combination of variant subdomains give rise to diversity of FGFRTK monomers. Divalent cations cooperate with the FGFRHS to conformationally restrict FGFRTK trans-phosphorylation, which causes depression of kinase activity and facilitates appropriate activation of the FGFR complex by FGF. Diffusional and conformational molecular models of the oligomeric FGFR complex are presented to explain how different point mutations in the FGFRTK commonly cause craniofacial and skeletal abnormalities of graded severity by graded increases in FGF-independent activity of total FGFR complexes. The role of the FGF family in liver growth and function and in prostate tumor progression is discussed.
Prog Nucleic Acid Res Mol Biol 1998
PMID:The heparan sulfate-fibroblast growth factor family: diversity of structure and function. 942 42

While prostate cancer is the most common malignant visceral neoplasm of men, its etiology remains largely unknown and its clinical course unpredictable. Molecular genetics of prostate cancer has become a fruitful area of investigation and might provide clues to understanding these phenomena. Mutation of the TP53 tumor suppressor gene (encoding the p53 protein) has been commonly reported as a critical event in human carcinogenesis, but recent findings in prostate cancer research call into question the correlation between TP53 mutation and prognosis for patients with this tumor. Whole-mount analysis has begun to address the histologic significance of the focal evolution of TP53 mutation in a pre-existing cancer and to reveal its role throughout the process of tumor progression. This model might also apply to other tumors.
Mol Med Today 1997 Nov
PMID:Molecular heterogeneity in prostate cancer: can TP53 mutation unravel tumorigenesis? 943 Jul 82

Transgenic mice expressing the polyomavirus (PyV) middle T antigen (MT) develop multifocal mammary tumors which frequently metastasize to the lung. The potent transforming activity of PyV MT is correlated with its capacity to activate and associate with a number of signaling molecules, including the Src family tyrosine kinases, the 85-kDa Src homology 2 subunit of the phosphatidylinositol 3' (PI-3') kinase, and the Shc adapter protein. To uncover the role of these signaling proteins in MT-mediated mammary tumorigenesis, we have generated transgenic mice that express mutant PyV MT antigens decoupled from either the Shc or the PI-3' kinase signaling pathway. In contrast to the rapid induction of metastatic mammary tumors observed in the strains expressing wild-type PyV MT, mammary epithelial cell-specific expression of either mutant PyV MT resulted in the induction of extensive mammary epithelial hyperplasias. The mammary epithelial hyperplasias expressing the mutant PyV MT defective in recruiting the PI-3' kinase were highly apoptotic, suggesting that recruitment of PI-3' kinase by MT affects cell survival. Whereas the initial phenotypes observed in both strains were global mammary epithelial hyperplasias, focal mammary tumors eventually arose in all female transgenic mice. Genetic and biochemical analyses of tumorigenesis in the transgenic strains expressing the PyV MT mutant lacking the Shc binding site revealed that a proportion of the metastatic tumors arising in these mice displayed evidence of reversion of the mutant Shc binding site. In contrast, no evidence of reversion of the PI-3' kinase binding site was noted in tumors derived from the strains expressing the PI-3' kinase binding site MT mutant. Tumor progression in both mutant strains was further correlated with upregulation of the epidermal growth factor receptor family members which are known to couple to the PI-3' kinase and Shc signaling pathways. Taken together, these observations suggest that PyV MT-mediated tumorigenesis requires activation of both Shc and PI-3' kinase, which appear to be required for stimulation of cell proliferation and survival signaling pathways, respectively.
Mol Cell Biol 1998 Apr
PMID:Requirement for both Shc and phosphatidylinositol 3' kinase signaling pathways in polyomavirus middle T-mediated mammary tumorigenesis. 952 4

Chromosome 11p15 has attracted considerable attention because of the biological importance of this region to human disease. Apart from being an important tumor suppressor locus showing loss of heterozygosity (LOH) in several adult and childhood cancers, 11p15 has been shown by linkage analysis to harbor the gene(s) for the Beckwith-Wiedemann syndrome. Furthermore, the clustering of known imprinted genes in the 11p15.5 region suggests that the target gene may also be imprinted. However, positional cloning efforts to identify the target genes have been complicated by the large size (approximately 10 Mb) and complexity of LOH at 11p15. Here, we have analyzed 94 matched normal and breast tumor samples using 17 polymorphic markers that map to 11p15.5-15.4. We have defined precisely the location of a breast tumor suppressor gene between the markers D11S1318 and D11S4088 (approximately 500 kb) within 11p15.5. LOH at this region occurred in approximately 35-45% of breast tumors analyzed. In addition, we have fine-mapped a second, critical region of LOH, that spans the markers D11S1338-D11S1323 (approximately 336 kb) at 11p15.5-p15.4, that is lost in approximately 55-60% of breast tumors. There is a striking correlation between the loss of the two 11p loci and the clinical and histopathological features of breast tumors. LOH at region 1 correlated significantly (P = 0.016) with early events in malignancy and invasiveness. In contrast, the loss of the more proximal region 2, is highly predictive (P = 0.012) of aggressive metastatic disease. Thus, two distinct tumor suppressor loci on chromosome 11p15 may contribute to tumor progression and metastasis in breast cancer. The fine mapping of this intriguing chromosomal region should facilitate the cloning of the target genes and provide critical clues to understanding the mechanisms that contribute to the evolution of adult and childhood cancers.
Hum Mol Genet 1998 May
PMID:Two distinct tumor suppressor loci within chromosome 11p15 implicated in breast cancer progression and metastasis. 953 95

Integrin alpha6beta4 is altered in many neoplastic cells, but no data exist to show this happens in esophageal neoplasms. To examine the expression of this integrin in rat esophageal tumorigenesis induced by N-nitrosomethylbenzylamine (NMBA), (alpha6 and beta4 expression was evaluated in normal esophageal epithelium, in NMBA-induced preneoplastic lesions, and in papillomas by quantitative reverse transcription (RT)-polymerase chain reaction (PCR) and immunohistochemical analysis. Because the 34 subunit of this integrin has been found to cause cell-cycle arrest by the induction of p21/WAF1/Cip1, the expression of p21/WAF1/Cip1 was also analyzed by RT-PCR. Compared with the levels in normal epithelium, the alpha6A, alpha6B, and beta4 integrin levels in esophageal papillomas were 1.9-, 2.2-, and 2.1-fold lower, respectively. RT-PCR analysis showed no significant differences in integrin levels between preneoplastic and normal samples, and northern blot analysis of the beta4 integrin produced results in agreement with the RT-PCR results. The p21/WAF1/Cip1 level was decreased 1.6-fold in preneoplastic tissues and 3.1-fold in papilloma samples when compared with the mRNA levels in normal epithelium. Immunostaining showed that alpha6beta4 integrin was localized at the basolateral surface of the basal cells in normal esophageal epithelium. In preneoplastic lesions, however, the expression of this integrin was not polarized and was expressed in basal cells as well as in suprabasal cells. Beta4 expression was significantly reduced and alpha6A expression was decreased and delocalized in papillomas. These findings suggest that alteration in alpha6beta4 integrin and p21/WAF1/Cip1 expression may be an important biomarker for tumor progression in NMBA-induced rat esophageal tumorigenesis.
Mol Carcinog 1998 Mar
PMID:Alterations in the expression of alpha6beta4 integrin and p21/WAF1/Cip1 in N-nitrosomethylbenzylamine-induced rat esophageal tumorigenesis. 953 50

Collagenase-1 (matrix metalloproteinase-1 (MMP-1)) degrades the extracellular matrix and enhances the invasive phenotype of tumor cells. v-src activated MMP-1 transcription through a series of elements in the proximal promoter, including the E2BP (nt -172), polyoma virus enhancer A3 (PEA3) (nt -94), activator protein-1 (AP-1) (nt -72), and signal transducer and activator of transcription (STAT) (nt -57) consensus sites. Of these sites, PEA3 and STAT contributed specifically to induction by v-src, whereas the remaining elements were also involved in induction by the phorbol ester phorbol myristate acetate (PMA). However, in contrast to MMP-1 induction by PMA, an AP-1 site located at nt -186 did not contribute to v-src induction. These results suggest divergence of the tyrosine kinase- and protein kinase C-dependent pathways with respect to MMP-1 transcription. v-src induced MMP-1 through mitogen-activated protein kinases, with extracellular signal-regulated kinases playing a larger role than c-jun N-terminal kinase. Retinoic acid, which inhibits the progression of certain cancers, repressed v-src-induced MMP-1 transcription. Constitutive expression of retinoic acid receptors (RARs) alpha or beta, but not gamma, or of retinoid X receptor alpha, repressed v-src-induced collagenase-1 transcription. We concluded that oncogenic induction of MMP-1 by v-src depends on signaling pathways and cis-acting sequences that are distinct from those involved in phorbol ester activation. Furthermore, v-src induction of MMP-1 may, by acting in concert with other genes, enhance matrix degradation and tumor progression, and retinoic acid and RARs may antagonize this induction in an RAR type-specific manner.
Mol Carcinog 1998 Mar
PMID:v-src activation of the collagenase-1 (matrix metalloproteinase-1) promoter through PEA3 and STAT: requirement of extracellular signal-regulated kinases and inhibition by retinoic acid receptors. 953 51

DNA repair defects might contribute both to cancer progression and to the extreme reactions to radiotherapy observed in approximately 5% of patients. Polymorphic microsatellites in three DNA repair genes, XRCC1, XRCC3 and XRCC5, were analyzed for possible linkage to cancer status or clinical radiosensitivity. XRCC1, 3 and 5 proteins are involved in single-strand DNA break rejoining, recombinational repair, and double-strand DNA break rejoining respectively. Mendelianly inherited microsatellite polymorphisms in these genes were analyzed in three groups: volunteers with no cancer history; radiosensitive cancer patients; cancer patients with acceptable reactions to radiotherapy. Rare heterozygous alterations in all three gene regions were found solely in the cancer subpopulation. Association testing between these rare polymorphisms and cancer status revealed a significant association for XRCC1 (P = 0.005), and XRCC3 (P = 0.004). There was also an association between these polymorphisms and clinical radiosensitivity for XRCC1 (P = 0.03), and XRCC3 (P = 0.005).
Somat Cell Mol Genet 1997 Jul
PMID:Rare microsatellite polymorphisms in the DNA repair genes XRCC1, XRCC3 and XRCC5 associated with cancer in patients of varying radiosensitivity. 954 26

Photochemotherapy employing 8-methoxypsoralen and ultraviolet radiation (PUVA) is widely used in the treatment of psoriasis. The photoactivation of psoralens in skin cells leads to DNA photoadduct formation which may be responsible for the efficacy of PUVA. Subsequent mutations may lead to the increased incidence of squamous cell carcinoma (SCC). Mutations in the p53 tumor suppressor gene have been detected in many human cancers. In this review, p53 mutation spectra in murine and human SCC are compared to those obtained from murine cells and skin treated with PUVA as well as to the p53 mutation spectrum in human solar SCC. While the expected psoralen-type mutations at alternating AT sites were detected in the treated cells and murine SCC (average frequency > 40%), such mutations were not commonly detected in the human SCC (< 10%). Other common mutations in the human SCC included: CG-->TA transitions (18%) and CG-->AT and TA-->GC transversions (17 and 25%, respectively). In addition, the frequency of UVB-type mutations at dipyrimidine sites (CC-->TT) in the SCC PUVA-treated psoriasis patients was comparable to that in patients with SCC from only solar exposure. A review of therapeutic history of these patients showed that many had also received UVB phototherapy. Furthermore, because sunlight is thought to be beneficial for psoriasis, nontherapeutic, casual UVB exposure cannot be excluded. Thus, the PUVA SCC may have arisen from the solar mutations and PUVA may enhance tumor progression by other epigenetic effects.
Environ Mol Mutagen 1998
PMID:Psoralen photochemotherapy, clinical efficacy, and photomutagenicity: the role of molecular epidemiology in minimizing risks. 954 88

In C3H/10T1/2 murine fibroblasts, overexpression of both c-Src and the human epidermal growth factor (EGF) receptor 1 (HER1) is required for detection of stable complexes between the two molecules and results in hyperactivation of the receptor and synergistic increases in tumor formation in nude mice, as compared with cells that overexpress only one of the pair. Elevated levels or activities of c-Src and HER1 also occur in a subset of later-stage breast cancers, suggesting that interactions between these two molecules could contribute to a more aggressive clinical course. To determine whether stable complexes between c-Src and HER1 occur in human breast cancers under the same conditions as in murine fibroblasts and whether the appearance of such complexes correlates with enhanced signaling through the EGF receptor and increased tumor growth, human breast tumor cell lines and tumor tissues were analyzed for a number of c-Src/HER1-mediated signaling events and tumorigenicity. In a panel of 14 cell lines, 10 overexpressed c-Src, and of these, five contained elevated levels of HER1 and exhibited an EGF-dependent association between HER1 and c-Src. This association was also present in a HER1/c-Src-overexpressing tumor sample from a breast cancer patient. Further analysis of signaling events revealed that phosphorylation of the HER1 substrate, Shc, and its downstream effector, mitogen-activated protein kinase, was increased in EGF-stimulated MDA-MB-468, MDA-MB-231, and BT-549 cells (which overexpress both c-Src and HER1) as compared with MCF7 and ZR-75-1 cells (which only overexpress c-Src). Furthermore, MDA-MB-468 and MDA-MB-231 cells displayed increased tumorigenicity in nude mice. These results support the hypothesis that c-Src/HER1 interactions contribute to tumor progression in certain late-stage breast tumor cells.
Mol Carcinog 1998 Apr
PMID:Characterization of human epidermal growth factor receptor and c-Src interactions in human breast tumor cells. 958 56


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