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PI3-kinase and PDK-1 regulate HDAC1-mediated transcriptional repression of transcription factor NF-kappaB

Yong Seok Choi1, Sunjoo Jeong

  • 1Department of Molecular Biology, Institute of Nanosensor and Biotechnology, Dankook University, Seoul 140-714, Korea.

Molecules and Cells
|November 4, 2005
PubMed

Insights

Phosphoinositide 3-kinase-dependent kinase 1 (PDK-1) activates nuclear factor kappa B (NF-kB) by removing HDAC1 repression. This PDK-1 mechanism contributes to NF-kB

Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Cancer Research

Background:

  • The PI3-kinase/Akt pathway regulates cell growth and survival.
  • NF-kB is crucial for immunity, inflammation, and anti-apoptosis.
  • The precise role of PDK-1 and PI3-kinase/Akt in NF-kB activation remains unclear.

Purpose of the Study:

  • To elucidate the role of PDK-1 in NF-kB transcriptional activation.
  • To investigate how PDK-1 influences the interaction between NF-kB and HDAC1.
  • To understand the contribution of the PI3-kinase/PDK-1 pathway to chemoresistance.

Main Methods:

  • Investigated PDK-1's effect on HDAC1 dissociation from NF-kB p65.
  • Assessed the impact of PDK-1 and PI3-kinase on CBP/p65 association.
  • Utilized etoposide to activate NF-kB via PI3-kinase/Akt and examined PDK-1's role.

Main Results:

  • PDK-1 dissociates the co-repressor HDAC1 from the NF-kB p65 subunit, promoting transcriptional activation.
  • PDK-1 and PI3-kinase did not directly modulate CBP association with p65.
  • Etoposide-induced NF-kB transcription was enhanced by wild-type PDK-1 and reduced by a dominant-negative PDK-1 mutant.

Conclusions:

  • PDK-1 activation relieves HDAC1-mediated repression of NF-kB.
  • This mechanism contributes to both basal and activated NF-kB transcription.
  • The PI3-kinase/PDK-1 pathway's role in NF-kB's anti-apoptotic function may explain chemoresistance in cancer cells.

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