SLIRP, a small SRA binding protein, is a nuclear receptor corepressor.
Steroid receptor RNA activator (SRA), the only known RNA coactivator, augments transactivation by nuclear receptors (NRs). We identified SLIRP (SRA stem-loop interacting RNA binding protein) binding to a functional substructure of SRA, STR7. SLIRP is expressed in normal and tumor tissues, contains an RNA recognition motif (RRM), represses NR transactivation in a SRA- and RRM-dependent manner, augments the effect of Tamoxifen, and modulates association of SRC-1 with SRA. SHARP, a RRM-containing corepressor, also binds STR7, augmenting repression with SLIRP. SLIRP colocalizes with SKIP (Chr14q24.3), another NR coregulator, and reduces SKIP-potentiated NR signaling. SLIRP is recruited to endogenous promoters (pS2 and metallothionein), the latter in a SRA-dependent manner, while NCoR promoter recruitment is dependent on SLIRP. The majority of the endogenous SLIRP resides in the mitochondria. Our data demonstrate that SLIRP modulates NR transactivation, suggest it may regulate mitochondrial function, and provide mechanistic insight into interactions between SRA, SLIRP, SRC-1, and NCoR.
Hatchell
Esme C
EC
Laboratory for Cancer Medicine, The University of Western Australia Centre for Medical Research, Western Australian Institute for Medical Research, Western Australia.
Colley
Shane M
SM
Beveridge
Dianne J
DJ
Epis
Michael R
MR
Stuart
Lisa M
LM
Giles
Keith M
KM
Redfern
Andrew D
AD
Miles
Lauren E C
LE
Barker
Andrew
A
MacDonald
Louisa M
LM
Arthur
Peter G
PG
Lui
James C K
JC
Golding
Jemma L
JL
McCulloch
Ross K
RK
Metcalf
Cecily B
CB
Wilce
Jackie A
JA
Wilce
Matthew C J
MC
Lanz
Rainer B
RB
O'Malley
Bert W
BW
Leedman
Peter J
PJ
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001943:Breast Neoplasms / Q000378:metabolism; D019556:COS Cells; D002522:Chlorocebus aethiops; D003001:Cloning, Molecular; D004268:DNA-Binding Proteins; D005260:Female; D006367:HeLa Cells; D051548:Histone Acetyltransferases; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008928:Mitochondria / Q000378:metabolism; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D056971:Nuclear Receptor Co-Repressor 1; D056920:Nuclear Receptor Coactivator 1; D011401:Promoter Regions, Genetic; D011487:Protein Conformation; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated / Q000235:genetics / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D016415:Sequence Alignment; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; C539127:NCOR1 protein, human; D009687:Nuclear Proteins; D056971:Nuclear Receptor Co-Repressor 1; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated; D016601:RNA-Binding Proteins; D012097:Repressor Proteins; C512286:SLIRP protein, human; C476510:SPEN protein, human; D014157:Transcription Factors; C405423:steroid receptor RNA activator; D051548:Histone Acetyltransferases; C538859:NCOA1 protein, human; D056920:Nuclear Receptor Coactivator 1