Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The most ominous development in tumor progression is the transition to an invasive and metastatic phenotype. Little is known, however, about the molecular alterations that cause a tumor to become invasive. In view of this, we have used microarray expression analysis to evaluate the expression profiles of a unique panel of human DU145 prostate cancer sublines that vary in their invasive potential. The three DU145 sublines expressed epidermal growth factor (EGF) receptors that differed in their ability to activate phospholipase C-gamma (PLC gamma). Three-way analyses yielded 11 genes out of 4608 genes screened that associated directly or inversely with invasive potential. The gene whose expression correlated most strongly with lack of invasion was identified as a potential invasion suppressor and called prostin-1. Pharmacological inhibition of PLC gamma (U73122) confirmed that PLC gamma signaling suppressed prostin-1 in that U73122 treatment caused induction of prostin-1 in PLC gamma competent cells. The prostin-1 gene, conserved through phylogeny, is induced by androgen in LNCaP cells and encodes a 92 amino acid protein. The protein shares no extensive homologies with other known genes, yet was recently identified as a small stabilizer subunit of the dolichol-phosphate-mannose (DPM) synthase complex. That DPM3/prostin-1 might suppress tumor progression was supported by the finding that exogenous expression in COS cells leads to apoptosis. These findings support the use of model cell lines to identify putative tumor suppressors and promoters.
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PMID:Dolichol-phosphate-mannose-3 (DPM3)/prostin-1 is a novel phospholipase C-gamma regulated gene negatively associated with prostate tumor invasion. 1142 Jun 90

Dolichol phosphate mannose synthase (DPMS) is an inverting GT-A-folded enzyme and classified as GT2 by CAZy. DPMS sequence carries a metal-binding DXD motif, a PKA motif, and a variable number of hydrophobic domains. Human and bovine DPMS possess a single transmembrane domain, whereas that from S. cerevisiae and A. thaliana carry multiple transmembrane domains and are superimposable. The catalytic activity of DPMS is documented in all spheres of life, and the 32kDa protein is uniquely regulated by protein phosphorylation. Intracellular activation of DPMS by cAMP signaling is truly due to the activation of the enzyme and not due to increased Dol-P level. The sequence of DPMS in some species also carries a protein N-glycosylation motif (Asn-X-Ser/Thr). Apart from participating in N-glycan biosynthesis, DPMS is essential for the synthesis of GPI anchor as well as for O- and C-mannosylation of proteins. Because of the dynamic nature, DPMS actively participates in cellular proliferation enhancing angiogenesis and breast tumor progression. In fact, overexpression of DPMS in capillary endothelial cells supports increased N-glycosylation, cellular proliferation, and enhanced chemotactic activity. These are expected to be completely absent in congenital disorders of glycosylation (CDGs) due to the silence of DPMS catalytic activity. DPMS has also been found to be involved in the cross talk with N-acetylglucosaminyl 1-phosphate transferase (GPT). Inhibition of GPT with tunicamycin downregulates the DPMS catalytic activity quantitatively. The result is impairment of surface N-glycan expression, inhibition of angiogenesis, proliferation of human breast cancer cells, and induction of apoptosis. Interestingly, nano-formulated tunicamycin is three times more potent in inhibiting the cell cycle progression than the native tunicamycin and is supported by downregulation of the ratio of phospho-p53 to total-p53 as well as phospho-Rb to total Rb. DPMS expression is also reduced significantly. However, nano-formulated tunicamycin does not induce apoptosis. We, therefore, conclude that DPMS could become a novel target for developing glycotherapy treating breast tumor in the clinic.
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PMID:Dynamic Function of DPMS Is Essential for Angiogenesis and Cancer Progression. 3063 1