title: JAZ (Znf346), a SIRT1-interacting protein, protects neurons by stimulating p21 (WAF/CIP1) protein expression.
abstract: SIRT1, a class III histone deacetylase, protects neurons in various models of neurodegenerative diseases. We previously described that neuroprotection by SIRT1 is independent of its catalytic activity. To elucidate how SIRT1 protects neurons, we performed a mass spectrometric screen to find SIRT1-interacting proteins. One of the proteins identified was JAZ (Znf346), a member of a new class of Cys-2-His-2 zinc finger proteins. To investigate the significance of JAZ in the regulation of neuronal survival, we overexpressed it in neurons. We found that JAZ protects cerebellar granule neurons against potassium deprivation-induced death and cortical neurons from death resulting from oxidative stress. JAZ also protects neurons against toxicity induced by mutant huntingtin and mutant ataxin-1 expression. Although expression of endogenous JAZ does not change in neurons primed to die, knockdown of its expression promotes death of otherwise healthy neurons. In contrast to its protective effect in neurons, overexpression of JAZ in different cell lines promotes death. We find that JAZ suppresses cell cycle progression, thereby explaining its contrasting effect in postmitotic neurons versus proliferating cell lines. Although not affecting the expression of several cyclins, overexpression of JAZ stimulates expression of p21 (WAF1/CIP1), a cell cycle inhibitor known to have neuroprotective effects. Results of chromatin immunoprecipitation and transcriptional assays indicate that the stimulatory effect of JAZ on p21 expression is mediated at the transcriptional level. Furthermore, knockdown of p21 expression inhibits the neuroprotective effect of JAZ. Together, our results suggest that JAZ protects neurons by inhibiting cell cycle re-entry through the transcriptional stimulation of p21 expression.
authors.affiliation: From the Department of Molecular and Cell Biology, University of Texas at Dallas, Richardson, Texas 75080 and the Department of Biological Sciences, Southern Methodist University, Dallas, Texas 75275.
authors.forename: Sathi
authors.initials: S
authors.lastname: Mallick
authors.affiliation: the Department of Biological Sciences, Southern Methodist University, Dallas, Texas 75275 sdmello@smu.edu.
authors.forename: Santosh R
authors.initials: SR
authors.lastname: D'Mello
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D015153:Blotting, Western; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology; D002540:Cerebral Cortex / Q000166:cytology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D057809:HEK293 Cells; D006801:Humans; D008856:Microscopy, Fluorescence; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011188:Potassium / Q000378:metabolism / Q000494:pharmacology; D011485:Protein Binding; D034622:RNA Interference; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; C493958:Cdkn1a protein, rat; D050759:Cyclin-Dependent Kinase Inhibitor p21; D009687:Nuclear Proteins; C000597030:Zfp346 protein, rat; C488368:Sirt1 protein, rat; D056564:Sirtuin 1; D011188:Potassium
keywords: Cell Cycle; Huntington Disease; Neurodegeneration; Neuroprotection; Sirtuin 1 (SIRT1)