title: Involvement of miR-196a in HIV-associated neurocognitive disorders.
abstract: Involvement of the human immunodeficiency virus type 1 (HIV-1) trans-activator of transcription (Tat) protein in neuronal deregulation and in the development of HIV-1 associated neurocognitive disorders (HAND) has been amply explored; however the mechanisms involved remain unclear. In search for the mechanisms, we demonstrated that Tat deregulates neuronal functions through a pathway that involved p73 and p53 pathway. We showed that Tat uses microRNA-196a (miR-196a) to deregulate the p73 pathway. Further, we found that the Abelson murine leukemia (c-Abl) phosphorylates p73 on tyrosine residue 99 (Tyr-99) in Tat-treated cells. Interestingly, Tat lost its ability to promote accumulation and phosphorylation of p73 in the presence of miR-196a mimic. Interestingly, accumulation of p73 did not lead to neuronal cell death by apoptosis as obtained by cell viability assay. Western blot analysis using antibodies directed against serine residues 807 and 811 of retinoblastoma (Rb) protein was also used to validate our data regarding lack of cell death. Hyperphosphorylation of RB (S807/811) is an indication of cell neuronal viability. These results highlight the key role played by p73 and microRNA in Tat-treated neurons leading to their deregulation and it deciphers mechanistically one of the pathways used by Tat to cause neuronal dysfunction that contributes to the development of HAND.
authors.affiliation: Molecular Studies of Neurodegenerative Diseases Lab, FELS Institute for Cancer Research & Molecular Biology, Temple University School of Medicine, PHA # 302, 3307 North Broad Street, Philadelphia, PA, 19140, USA.
authors.forename: Asen
authors.initials: A
authors.lastname: Bagashev
authors.forename: Ruma
authors.initials: R
authors.lastname: Mukerjee
authors.forename: Maryline
authors.initials: M
authors.lastname: Santerre
authors.forename: Fabiola E
authors.initials: FE
authors.lastname: Del Carpio-Cano
authors.forename: Jenny
authors.initials: J
authors.lastname: Shrestha
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: Johnny J
authors.initials: JJ
authors.lastname: He
authors.forename: Bassel E
authors.initials: BE
authors.lastname: Sawaya
mesh_terms: D000818:Animals; D017209:Apoptosis; D016923:Cell Death; D045744:Cell Line, Tumor; D002470:Cell Survival; D003072:Cognition Disorders / Q000209:etiology / Q000378:metabolism* / Q000821:virology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D015658:HIV Infections / Q000150:complications / Q000378:metabolism* / Q000821:virology; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D016315:Proto-Oncogene Proteins c-abl / Q000235:genetics / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000378:metabolism; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; C542543:MIRN196 microRNA, human; D035683:MicroRNAs; D009687:Nuclear Proteins; D016160:Retinoblastoma Protein; C000606460:TP73 protein, human; C000606368:Trp73 protein, mouse; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D054322:tat Gene Products, Human Immunodeficiency Virus; D016315:Proto-Oncogene Proteins c-abl