Nuclear factor κB functions as a negative regulator for the rat androgen receptor gene and NF-κB activity increases during the age-dependent desensitization of the liver

P. C. Supakar, M. H. Jung, C. S. Song, B. Chatterjee, A. K. Roy

Research output: Contribution to journalArticle

137 Scopus citations

Abstract

Transcriptional regulation of the steroid hormone receptor genes plays a central role in temporal changes of target cell sensitivity during development, maturation, and aging. Sequence-specific DNA-protein interactions mediate these regulatory functions. Progressive 5' deletion of the rat androgen receptor (rAR) gene immediately beyond the -572 base pair (bp) region causes a marked increase in its promoter activity. DNase I footprinting with nuclear proteins revealed a protected area encompassing - 574- to -554-bp positions that begins with a perfectly palindromic nuclear factor κB (NF-κB) motif. Electrophoretic mobility shift analyses (EMSA) showed that the decameric rAR NF-κB site at positions -574 to -565 cross- competes with the authentic κ immunoglobulin light chain enhancer for specific protein binding. Supershift with specific antibodies to NF-κB subunits confirmed that the two retarded bands observed in the EMSA with the labeled rAR probe are due to p50/p65 and p50/p50 dimers of the NF-κB/Rel proteins. Fragments of rAR promoter with either deletion or point mutation of the NF-κB site are found to be about 2- to 3-fold more effective as compared to the wild type control in driving a heterologous reporter gene in cellulo. Thus, unlike most other known cases, NF-κB acts as a negative regulator for the rAR gene. The physiological relevance of this repressor function is evident from a 10-fold increase in the p50/p50 form of the NF-κB activity in the liver of aged rats exhibiting hepatic androgen desensitization. The newly identified repressor element is a rare example of a naturally occurring perfect palindromic binding motif for the NF-κB/Rel family of transcription factors. This repressor factor and the positively acting age-dependent factor, ADF, described earlier (Supakar, P. C., Song, C. S., Jung, M. H., Slomczynska, M. A., Kim, J.-M., Vellanoweth, R. L., Chatterjee, B. and Roy, A. K. (1993) J. Biol. Chem. 268, 26400-26408) function to coordinate the tissue-specific down-regulation of the rAR gene during aging.

Original languageEnglish (US)
Pages (from-to)837-842
Number of pages6
JournalJournal of Biological Chemistry
Volume270
Issue number2
DOIs
StatePublished - 1995

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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