Co-activator SRC-1 is dispensable for transcriptional control by STAT3.
SRC (steroid receptor co-activator)-1 has been reported to interact with and to be an essential co-activator for several members of the STAT (signal transducer and activator of transcription) family, including STAT3, the major signal transducer of IL (interleukin)-6. We addressed the question of whether SRC-1 is crucial for IL-6- and STAT3-mediated physiological responses such as myeloma cell survival and acute-phase protein induction. In fact, silencing of SRC-1 by RNA interference rapidly induced apoptosis in IL-6-dependent INA-6 human myeloma cells, comparable with what was observed upon silencing of STAT3. Using chromatin immunoprecipitation at STAT3 target regions of various genes, however, we observed constitutive binding of SRC-1 that decreased when INA-6 cells were treated with IL-6. The same held true for STAT3 target genes analysed in HepG2 human hepatocellular carcinoma cells. SRC-1-knockdown studies demonstrated that STAT3-controlled promoters require neither SRC-1 nor the other p160 family members SRC-2 or SRC-3 in HepG2 cells. Furthermore, microarray expression profiling demonstrated that the responsiveness of IL-6 target genes is not affected by SRC-1 silencing. In contrast, co-activators of the CBP [CREB (cAMP-response element-binding protein)-binding protein]/p300 family proved functionally important for the transactivation potential of STAT3 and bound inducibly to STAT3 target regions. This recruitment did not depend on the presence of SRC-1. Altogether, this suggests that functional impairment of STAT3 is not involved in the induction of myeloma cell apoptosis by SRC-1 silencing. We therefore conclude that STAT3 transactivates its target genes by the recruitment of CBP/p300 co-activators and that this process generally does not require the contribution of SRC-1.
Cvijic
Helena
H
Institute of Clinical Immunology and Transfusion Medicine, University of Leipzig, Johannisallee 30, 04103 Leipzig, Germany.
Bauer
Kay
K
Löffler
Dennis
D
Pfeifer
Gabriele
G
Blumert
Conny
C
Kretzschmar
Antje K
AK
Henze
Christian
C
Brocke-Heidrich
Katja
K
Horn
Friedemann
F
D045744:Cell Line, Tumor; D050881:E1A-Associated p300 Protein / Q000378:metabolism*; D020868:Gene Silencing; D051548:Histone Acetyltransferases / Q000235:genetics / Q000502:physiology*; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology; D056920:Nuclear Receptor Coactivator 1; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic; D015533:Transcriptional Activation
D015850:Interleukin-6; D050796:STAT3 Transcription Factor; D014157:Transcription Factors; D050881:E1A-Associated p300 Protein; D051548:Histone Acetyltransferases; C538859:NCOA1 protein, human; D056920:Nuclear Receptor Coactivator 1