Filamin-A fragment localizes to the nucleus to regulate androgen receptor and coactivator functions.
The androgen receptor (AR), a nuclear transcription factor, mediates male sexual differentiation, and its excessive action is associated with prostate cancer. We have characterized a negative regulatory domain in the AR hinge region, which interacted with filamin A (FLNa), an actin-binding cytoskeletal protein. FLNa interfered with AR interdomain interactions and competed with the coactivator transcriptional intermediary factor 2 to specifically down-regulate AR function. Although full-length FLNa was predominantly cytoplasmic, a C-terminal 100-kDa fragment of FLNa colocalized with AR to the nucleus. This naturally occurring FLNa fragment repressed AR transactivation and disrupted AR interdomain interactions and transcriptional intermediary factor 2-activated AR function in a manner reminiscent of full-length FLNa, raising the possibility that the inhibitory effects of cytoplasmic FLNa may be transduced through this fragment, which can localize to the nucleus and form part of the pre-initiation complex. This unanticipated role of FLNa adds to the growing evidence for the involvement of cytoskeletal proteins in transcription regulation.
Loy
C J
CJ
Department of Obstetrics and Gynecology, National University of Singapore, Singapore 119074.
Sim
K S
KS
Yong
E L
EL
D000595:Amino Acid Sequence; D001665:Binding Sites; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D003285:Contractile Proteins / Q000737:chemistry / Q000378:metabolism*; D064448:Filamins; D006367:HeLa Cells; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008840:Microfilament Proteins / Q000737:chemistry / Q000378:metabolism*; D008954:Models, Biological; D008969:Molecular Sequence Data; D009154:Mutation; D051958:Nuclear Receptor Coactivator 2; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011944:Receptors, Androgen / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D020798:Two-Hybrid System Techniques
D003285:Contractile Proteins; D064448:Filamins; D008840:Microfilament Proteins; D051958:Nuclear Receptor Coactivator 2; D010446:Peptide Fragments; D011944:Receptors, Androgen; D011994:Recombinant Proteins; D014157:Transcription Factors