PI3-kinase and PDK-1 regulate HDAC1-mediated transcriptional repression of transcription factor NF-kappaB.
PDK-1 activates PI3-kinase/Akt signaling and regulates fundamental cellular functions, such as growth and survival. NF-kB is involved in the induction of a variety of cellular genes affecting immunity, inflammation and the resistance to apoptosis induced by some anti-cancer drugs. Even though the crucial involvement of the PI3-kinase/Akt pathway in the anti-apoptotic activation of NF-kB is well known, the exact role of PDK-1 as well as PI3-kinase/Akt in NF-kB activation is not understood. Here we demonstrate that PDK-1 plays a pivotal role in transcriptional activation of NF-kB by dissociating the transcriptional co-repressor HDAC1 from the p65 subunit of NF-kB. The association of CBP with p65 was not directly modulated by PDK-1 or by PI3-kinase. Etoposide activated NF-kB through PI3-kinase/Akt, and the transcription activation domain (TAD) of p65 was further activated by wild-type PDK-1. Overexpression of a dominant negative PDK-1 mutant decreased etoposide-induced NF-kB transcription and further down-regulated the ectopic HDAC1-mediated decrease in NF-kB transcriptional activity. Thus activation of PDK-1 relieves the HDAC1-mediated repression of NF-kB that may be related to basal as well as activated transcription by NF-kB. This effect may also explain the role of the PI3-kinase/PDK-1 pathway in the anti-apoptotic function of NF-kB associated with the chemoresistance of cancer cells.
Choi
Yong Seok
YS
Department of Molecular Biology, Institute of Nanosensor and Biotechnology, Dankook University, Seoul 140-714, Korea.
Jeong
Sunjoo
S
D064413:3-Phosphoinositide-Dependent Protein Kinases; D002478:Cells, Cultured; D005047:Etoposide / Q000494:pharmacology; D006367:HeLa Cells; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D020935:MAP Kinase Signaling System; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection; D050880:p300-CBP Transcription Factors / Q000378:metabolism
D064413:3-Phosphoinositide-Dependent Protein Kinases; D005047:Etoposide; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D012097:Repressor Proteins; D051996:Transcription Factor RelA; D050880:p300-CBP Transcription Factors; C110550:HDAC1 protein, human