Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P11021 (BiP)
 2,049 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Stearoyl-CoA desaturase (SCD, SCD1), an endoplasmic reticulum (ER) resident protein and a rate-limiting enzyme in monounsaturated fatty acid biosynthesis, regulates cellular functions by controlling the ratio of saturated to monounsaturated fatty acids. Increase in SCD expression is strongly implicated in the proliferation and survival of cancer cells, whereas its decrease is known to impair proliferation, induce apoptosis, and restore insulin sensitivity. We examined whether fenretinide, (N-(4-hydroxyphenyl)retinamide, 4HPR), which induces apoptosis in cancer cells and recently shown to improve insulin sensitivity, can modulate the expression of SCD. We observed that fenretinide decreased SCD protein and enzymatic activity in the ARPE-19 human retinal pigment epithelial cell line. Increased expression of BiP/GRP78, ATF4, and GADD153 implicated ER stress. Tunicamycin and thapsigargin, compounds known to induce ER stress, also decreased the SCD protein. This decrease was completely blocked by the proteasome inhibitor MG132. In addition, PYR41, an inhibitor of ubiquitin activating enzyme E1, blocked the fenretinide-mediated decrease in SCD. Immunoprecipitation analysis using anti-ubiquitin and anti-SCD antibodies and the blocking of SCD loss by PYR41 inhibition of ubiquitination further corroborate that fenretinide mediates the degradation of SCD in human RPE cells via the ubiquitin-proteasome dependent pathway. Therefore, the effect of fenretinide on SCD should be considered in its potential therapeutic role against cancer, type-2 diabetes, and retinal diseases.
 ...
PMID:Fenretinide induces ubiquitin-dependent proteasomal degradation of stearoyl-CoA desaturase in human retinal pigment epithelial cells. 2435 7

ORCTL3, an organic cation/anion transporter expressed in various tissue types, was isolated in a genome-wide cDNA screen as a gene with a tumor-specific apoptosis activity. When overexpressed it elicits an apoptosis response in many transformed cells, while normal cells remain unaffected. It can be activated for apoptosis induction by individual tumorigenic mutations in renal cells. This effect is independent of the tumor cells' proliferation status and mediated by an incomplete ER stress response, characterized by the accumulation of the endoplasmic reticulum-stress marker ATF4, but not BiP. Recent studies show that for its apoptosis induction activity ORCTL3 targets the enzyme stearoyl-CoA desaturase-1 (SCD-1) that is involved in the fatty acid metabolism. This is evidenced by the inhibition of apoptosis induced through ORCTL3 when the SCD-1 product oleic acid is exogenously supplemented or when SCD-1 is co-transfected in the transformed cells. ORCTL3's activity to specifically target tumor cells is caused by the transmembrane domains 3 and 4 of the mouse, but not the human, gene. In an in vivo model ORCTL3 shows a significant shrinkage in the size of xenograft tumors when injected with an adenoviral carrier carrying the mouse ORCTL3 gene. An ex vivo study using human renal cancer cells confirmed the promising tumor-specific apoptosis effect of ORCTL3. Since ORCTL3 targets fatty acid metabolism in transformed cells and induces an ER stress specifically in these cells, it reveals a novel therapeutic interference option for tumor cells.
...
PMID:Isolation and characterization of the anticancer gene organic cation transporter like-3 (ORCTL3). 2500 39