Agonist-mediated docking of androgen receptor onto the mitotic chromatin platform discriminates intrinsic mode of action of prostate cancer drugs

Sanjay Kumar, Nagendra K. Chaturvedi, Subodh Kumar, Rakesh K. Tyagi

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

This study documents the analysis of a hitherto unreported dynamic behavior of androgen receptor (AR), a member of the nuclear receptor superfamily. Employing GFP-tagged AR, we observed agonist-mediated docking of AR onto the mitotic chromatin during all the stages of mitosis. When bound to therapeutic drugs with intrinsically absolute or partial agonistic properties, AR concomitantly associated with the mitotic chromatin. Conversely, pure antagonists known to bind and subsequently translocate unliganded AR from cytoplasm to nuclear compartment did not provoke such association. The agonist-mediated docking of AR could not be competed with other transcription factors that constitutively preoccupied the chromosomal docking sites. Amongst the previously reported proteins, AR is first example of a transcription factor whose response on mitotic chromatin platform can be modulated in a ligand-specific manner. However, data from live cell imaging revealed that co-activators of agonist-activated receptor that are recruited into "nuclear foci" of interphase chromatin are dislodged from the mitotic chromatin during cell division. This implies that in absence of critical co-activators, AR transverses mitotic phase in transcriptionally silenced state. Finally, our results indicate that ligand-mediated dynamic relationship of nuclear receptors with mitotic chromatin can be effectively exploited to study, analyze and authenticate therapeutic ligands.

Original languageEnglish (US)
Pages (from-to)59-73
Number of pages15
JournalBiochimica et Biophysica Acta - Molecular Cell Research
Volume1783
Issue number1
DOIs
StatePublished - Jan 2008

Keywords

  • Antiandrogen
  • Mitotic chromatin
  • Prostate cancer
  • Steroid receptor

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'Agonist-mediated docking of androgen receptor onto the mitotic chromatin platform discriminates intrinsic mode of action of prostate cancer drugs'. Together they form a unique fingerprint.

Cite this