PMID- 17255101 OWN - NLM STAT- MEDLINE DCOM- 20070531 LR - 20211203 IS - 0021-9258 (Print) IS - 0021-9258 (Linking) VI - 282 IP - 16 DP - 2007 Apr 20 TI - p21-activated kinase 1 is activated through the mammalian target of rapamycin/p70 S6 kinase pathway and regulates the replication of hepatitis C virus in human hepatoma cells. PG - 11836-48 AB - Cellular mechanisms that regulate the replication of hepatitis C virus (HCV) RNA are poorly understood. p21-activated kinase 1 (PAK1) is a serine/threonine kinase that has been suggested to participate in antiviral signaling. We studied its role in the cellular control of HCV replication. Transfection of PAK1-specific small interfering RNA enhanced viral RNA and protein abundance in established replicon cell lines as well as cells infected with chimeric genotype 1a/2a HCV, despite reducing cellular proliferation, suggesting specific regulation of HCV replication. PAK1 knockdown did not reduce interferon regulatory factor 3-dependent gene expression, indicating that this regulation is independent of the retinoic acid-inducible gene I/interferon regulatory factor 3 pathway. On the other hand, LY294002 and rapamycin abolished PAK1 phosphorylation and enhanced HCV abundance, suggesting that the mammalian target of rapamycin (mTOR) is involved in PAK1 regulation of HCV. Small interfering RNA knockdown of the mTOR substrate p70 S6 kinase abrogated PAK1 phosphorylation and enhanced HCV RNA abundance, whereas overexpression of a constitutively active alternate substrate, eukaryotic translation initiation factor 4E-binding protein 1, increased cap-independent viral translation and viral RNA abundance without influencing PAK1 phosphorylation. Similar data indicated that mTOR is regulated by both phosphatidylinositol 3-kinase/Akt and ERK. Taken together, the data indicate that p70 S6 kinase activates PAK1 and contributes to phosphatidylinositol 3-kinase- and ERK-mediated regulation of HCV RNA replication. FAU - Ishida, Hisashi AU - Ishida H AD - Center for Hepatitis Research, Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, Texas 77555-1018, USA. FAU - Li, Kui AU - Li K FAU - Yi, Minkyung AU - Yi M FAU - Lemon, Stanley M AU - Lemon SM LA - eng GR - R21-AI063451/AI/NIAID NIH HHS/United States GR - R21-DA018054/DA/NIDA NIH HHS/United States GR - U19-AI40035/AI/NIAID NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20070125 PL - United States TA - J Biol Chem JT - The Journal of biological chemistry JID - 2985121R RN - 0 (Chromones) RN - 0 (Morpholines) RN - 31M2U1DVID (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one) RN - EC 2.7.- (Protein Kinases) RN - EC 2.7.1.1 (MTOR protein, human) RN - EC 2.7.11.1 (PAK1 protein, human) RN - EC 2.7.11.1 (Protein Serine-Threonine Kinases) RN - EC 2.7.11.1 (Ribosomal Protein S6 Kinases) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - EC 2.7.11.1 (p21-Activated Kinases) RN - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases) RN - W36ZG6FT64 (Sirolimus) SB - IM MH - Carcinoma, Hepatocellular/*metabolism MH - Cell Line, Tumor MH - Cell Proliferation MH - Chromones/pharmacology MH - Extracellular Signal-Regulated MAP Kinases/metabolism MH - Hepacivirus/*metabolism MH - Humans MH - Models, Biological MH - Morpholines/pharmacology MH - Phosphatidylinositol 3-Kinases/metabolism MH - Promoter Regions, Genetic MH - Protein Kinases/*metabolism MH - Protein Serine-Threonine Kinases/metabolism/*physiology MH - Ribosomal Protein S6 Kinases/*metabolism MH - Sirolimus/pharmacology MH - TOR Serine-Threonine Kinases MH - Virus Replication MH - p21-Activated Kinases EDAT- 2007/01/27 09:00 MHDA- 2007/06/01 09:00 CRDT- 2007/01/27 09:00 PHST- 2007/01/27 09:00 [pubmed] PHST- 2007/06/01 09:00 [medline] PHST- 2007/01/27 09:00 [entrez] AID - S0021-9258(19)58165-0 [pii] AID - 10.1074/jbc.M610106200 [doi] PST - ppublish SO - J Biol Chem. 2007 Apr 20;282(16):11836-48. doi: 10.1074/jbc.M610106200. Epub 2007 Jan 25.