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Multiple cyclin kinase inhibitors promote bile acid-induced apoptosis and autophagy in primary hepatocytes via p53-CD95-dependent signaling. 2008

Guo Zhang, and Margaret A Park, and Clint Mitchell, and Teneille Walker, and Hossein Hamed, and Elaine Studer, and Martin Graf, and Mohamed Rahmani, and Seema Gupta, and Philip B Hylemon, and Paul B Fisher, and Steven Grant, and Paul Dent
Department of Biochemistry, Virginia Commonwealth University, Richmond, Virginia 23298-0035, USA.

Previously, using primary hepatocytes residing in early G1 phase, we demonstrated that expression of the cyclin-dependent kinase (CDK) inhibitor protein p21Cip-1/WAF1/mda6 (p21) enhanced the toxicity of deoxycholic acid (DCA) + MEK1/2 inhibitor. This study examined the mechanisms regulating this apoptotic process. Overexpression of p21 or p27(Kip-1) (p27) enhanced DCA + MEK1/2 inhibitor toxicity in primary hepatocytes that was dependent on expression of acidic sphingomyelinase and CD95. Overexpression of p21 suppressed MDM2, elevated p53 levels, and enhanced CD95, BAX, NOXA, and PUMA expression; knockdown of BAX/NOXA/PUMA reduced CDK inhibitor-stimulated cell killing. Parallel to cell death processes, overexpression of p21 or p27 profoundly enhanced DCA + MEK1/2 inhibitor-induced expression of ATG5 and GRP78/BiP and phosphorylation of PKR-like endoplasmic reticulum kinase (PERK) and eIF2alpha, and it increased the numbers of vesicles containing a transfected LC3-GFP construct. Incubation of cells with 3-methyladenine or knockdown of ATG5 suppressed DCA + MEK1/2 inhibitor-induced LC3-GFP vesicularization and enhanced DCA + MEK1/2 inhibitor-induced toxicity. Expression of dominant negative PERK blocked DCA + MEK1/2 inhibitor-induced expression of ATG5, GRP78/BiP, and eIF2alpha phosphorylation and prevented LC3-GFP vesicularization. Knock-out or knockdown of p53 or CD95 abolished DCA + MEK1/2 inhibitor-induced PERK phosphorylation and prevented LC3-GFP vesicularization. Thus, CDK inhibitors suppress MDM2 levels and enhance p53 expression that facilitates bile acid-induced, ceramide-dependent CD95 activation to induce both apoptosis and autophagy in primary hepatocytes.

UI MeSH Term Description Entries
D008297 Male Males
D008869 Microtubule-Associated Proteins High molecular weight proteins found in the MICROTUBULES of the cytoskeletal system. Under certain conditions they are required for TUBULIN assembly into the microtubules and stabilize the assembled microtubules. Ensconsin,Epithelial MAP, 115 kDa,Epithelial Microtubule-Associate Protein, 115 kDa,MAP4,Microtubule Associated Protein,Microtubule Associated Protein 4,Microtubule Associated Protein 7,Microtubule-Associated Protein,Microtubule-Associated Protein 7,E-MAP-115,MAP1 Microtubule-Associated Protein,MAP2 Microtubule-Associated Protein,MAP3 Microtubule-Associated Protein,Microtubule Associated Proteins,Microtubule-Associated Protein 1,Microtubule-Associated Protein 2,Microtubule-Associated Protein 3,7, Microtubule-Associated Protein,Associated Protein, Microtubule,E MAP 115,Epithelial Microtubule Associate Protein, 115 kDa,MAP1 Microtubule Associated Protein,MAP2 Microtubule Associated Protein,MAP3 Microtubule Associated Protein,Microtubule Associated Protein 1,Microtubule Associated Protein 2,Microtubule Associated Protein 3,Microtubule-Associated Protein, MAP1,Microtubule-Associated Protein, MAP2,Microtubule-Associated Protein, MAP3,Protein 7, Microtubule-Associated,Protein, Microtubule Associated,Protein, Microtubule-Associated
D010766 Phosphorylation The introduction of a phosphoryl group into a compound through the formation of an ester bond between the compound and a phosphorus moiety. Phosphorylations
D002478 Cells, Cultured Cells propagated in vitro in special media conducive to their growth. Cultured cells are used to study developmental, morphologic, metabolic, physiologic, and genetic processes, among others. Cultured Cells,Cell, Cultured,Cultured Cell
D002756 Cholagogues and Choleretics Gastrointestinal agents that stimulate the flow of bile into the duodenum (cholagogues) or stimulate the production of bile by the liver (choleretic). Choleretics,Cholagogues,Cholagogues, Choleretics,Choleretics and Cholagogues,Hydrocholeretics
D003840 Deoxycholic Acid A bile acid formed by bacterial action from cholate. It is usually conjugated with glycine or taurine. Deoxycholic acid acts as a detergent to solubilize fats for intestinal absorption, is reabsorbed itself, and is used as a choleretic and detergent. Deoxycholate,Desoxycholic Acid,Kybella,Choleic Acid,Deoxycholic Acid, 12beta-Isomer,Deoxycholic Acid, 3beta-Isomer,Deoxycholic Acid, 5alpha-Isomer,Deoxycholic Acid, Disodium Salt,Deoxycholic Acid, Magnesium (2:1) Salt,Deoxycholic Acid, Monoammonium Salt,Deoxycholic Acid, Monopotassium Salt,Deoxycholic Acid, Monosodium Salt,Deoxycholic Acid, Sodium Salt, 12beta-Isomer,Dihydroxycholanoic Acid,Lagodeoxycholic Acid,Sodium Deoxycholate,12beta-Isomer Deoxycholic Acid,3beta-Isomer Deoxycholic Acid,5alpha-Isomer Deoxycholic Acid,Deoxycholate, Sodium,Deoxycholic Acid, 12beta Isomer,Deoxycholic Acid, 3beta Isomer,Deoxycholic Acid, 5alpha Isomer
D000071187 Autophagy-Related Protein 5 An autophagy-related protein that functions in AUTOPHAGOSOME biogenesis. It is conjugated to the ATG12 PROTEIN via a process that is similar to UBIQUITINATION and involves the ATG7 PROTEIN and ATG10 enzyme. The ATG12-ATG5 conjugate acts as an E3 UBIQUITIN LIGASE-like enzyme and is required for the localization of ATG8 PROTEINS to AUTOPHAGOSOME vesicle membranes and modification of membrane lipids. ATG-5 Protein,ATG5 Protein,Apoptosis-Specific Protein,Autophagy Protein-5,Autophagy-Related 5 Protein,ATG 5 Protein,Apoptosis Specific Protein,Autophagy Protein 5,Autophagy Related 5 Protein,Autophagy Related Protein 5
D000091342 Endoplasmic Reticulum Chaperone BiP An ENDOPLASMIC RETICULUM specific chaperone of the HSP70 family. They are involved in folding and oligomerization of secreted and membrane proteins and ENDOPLASMIC RETICULUM STRESS related UNFOLDED PROTEIN RESPONSE. Binding-immunoglobulin Protein Molecular Chaperone,Glucose Regulated Protein 78 kDa,Grp78,HSPA5 Protein,Heat-Shock Protein 5,Molecular Chaperone BiP,Molecular Chaperone GRP78,BiP, Molecular Chaperone,Binding immunoglobulin Protein Molecular Chaperone,GRP78, Molecular Chaperone,Heat Shock Protein 5,Protein, HSPA5
D000225 Adenine A purine base and a fundamental unit of ADENINE NUCLEOTIDES. Vitamin B 4,4, Vitamin B,B 4, Vitamin
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia

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