Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:6.3.2.19 (ubiquitin-protein ligase)
 799 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Lung cancers are a heterogeneous group of tumors broadly classified as small cell or non-small cell lung cancers. In each case, numerous DNA mutations precede tumor formation, resulting in the activation of growth stimulatory genes and the loss of tumor suppressor genes. The known cellular functions of the tumor suppressor genes most commonly affected in lung cancer are reviewed herein, including the retinoblastoma (Rb) gene on chromosome 13q14, the p53 gene on 17p13, and the cyclin-dependent kinase inhibitor (CDKN2) gene on 9p21. The chromosomal locations for other potential tumor suppressor genes are on chromosomes 3p, 9p, and 11p. Candidate genes in these regions include the von Hippel-Lindau (VHL) gene at 3p25, the ubiquitin-activating enzyme homologue (UBE1L at 3p21, the genes for the dinucleoside polyphosphate hydrolase FHIT and receptor protein-tyrosine phosphatase gamma PTPRG at 3p14.2, the genes for tropomyosin beta (TM1) and a talin homologue (talin) at 9p21, and the H-ras gene at 11p15.
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PMID:Hot spots for molecular genetic alterations in lung cancer. 989 Dec 28

Reduced expression level of p27, a cyclin-dependent kinase inhibitor, is associated with high aggressiveness and poor prognosis of various malignant tumors, including gastric carcinoma. S-phase kinase-associated protein 2 (Skp2), a member of the F-box family of substrate-recognition subunits of Skp1-Cullin-F-box ubiquitin-protein ligase complexes, is necessary for p27 ubiquitination and degradation. In the present study, we examined the clinical and biological significance of Skp2 expression in human gastric carcinoma and the relationship between the expression of Skp2 and p27. Northern blot analysis showed that Skp2 mRNA was overexpressed in carcinoma tissues (P < 0.05), and the high Skp2 expression group showed significantly poorer prognosis in 98 patients with gastric carcinoma (P < 0.05). Immunohistochemical analysis showed that Skp2 protein was expressed predominantly in carcinoma cells. We also found an inverse correlation between the expression of Skp2 mRNA and p27 protein in vivo (P < 0.01). To analyze the biological behavior of Skp2, we established stably Skp2-transfected gastric carcinoma cell lines. Western blot analysis showed that Skp2-transfected cells expressed lower levels of p27 protein than the control cells. Skp2-transfected cells showed significantly higher levels of growth rate (P < 0.05), percentage of bromodeoxyuridine-positive cells after serum starvation (P < 0.01), resistance to apoptosis induction by actinomycin D treatment (P < 0.05), and invasion potential (P < 0.01) than the control cells. These findings indicate that Skp2 expression can modulate the malignant phenotype of gastric carcinoma, possibly via p27 proteolysis. Skp2 can play an important role in gastric carcinoma progression and would be a novel target for the treatment of gastric carcinoma as well as a strong prognostic marker.
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PMID:Clinical and biological significance of S-phase kinase-associated protein 2 (Skp2) gene expression in gastric carcinoma: modulation of malignant phenotype by Skp2 overexpression, possibly via p27 proteolysis. 1209 95

S-phase kinase associated protein 2 (Skp2) is a member of an F-box family of substrate-recognition subunits of SCF ubiquitin-protein ligase complexes that has been implicated in the ubiquitin-mediated degradation of several key regulators of mammalian G1 progression, including the cyclin-dependent kinase inhibitor p27Kip1, a dosage-dependent tumor suppressor protein. The anti-sense effect was confirmed in two cell lines of oral cancer cells that also exhibited over-expression of the Skp2 protein. In this study, we examined the mechanism responsible for anti-sense-mediated growth inhibition of oral cancer cells in vitro and in vivo. Skp2-anti-sense treatment induced apoptosis characterized by an increase in the early apoptosis, fragmentation of nuclei and activation of caspase-3, -8 and -9. Moreover, the growth of xenograft tumors was markedly suppressed by Skp2-anti-sense treatment. Furthermore, histological specimen revealed apoptotic cell death was increased in Skp2-anti-sense treated tumors. Our results suggest that down-regulation of Skp2 appears to induce apoptosis in oral cancer cells, targeting this molecule could represent a promising new therapeutic approach for this type of cancer.
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PMID:Down-regulation of S-phase kinase associated protein 2 (Skp2) induces apoptosis in oral cancer cells. 1605 17