Collaboration of signal transducer and activator of transcription 1 (STAT1) and BRCA1 in differential regulation of IFN-γ target genes

Collaboration of signal transducer and activator of transcription 1 (STAT1) and BRCA1 in differential regulation of IFN-γ target genes

^†Derald H. Ruttenberg Cancer Center, and ^‡Immunobiology Center, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029; and ^§Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Institute of Medicine and Harvard Medical School, Boston, MA 02115

Edited by James E. Darnell, Jr., The Rockefeller University, New York, NY, and approved February 23, 2000 (received for review October 29, 1999)

Abstract

Most of the activities of IFN-γ are the result of STAT1-mediated transcriptional responses. In this study, we show that the BRCA1 tumor suppressor acts in concert with STAT1 to differentially activate transcription of a subset of IFN-γ target genes and mediates growth inhibition by this cytokine. After IFN-γ treatment, induction of the cyclin-dependent kinase inhibitor, p21WAF1, was synergistically activated by BRCA1, whereas the IRF-1 gene was unaffected. Importantly, the differential induction of p21WAF1 was impaired in breast cancer cells homozygous for the mutant BRCA1 5382C allele. Biochemical analysis illustrated that the mechanism of this transcriptional synergy involves interaction between BRCA1 aa 502–802 and the C-terminal transcriptional activation domain of STAT1 including Ser-727 whose phosphorylation is crucial for transcriptional activation. Significantly, STAT1 proteins mutated at Ser-727 bind poorly to BRCA1, reinforcing the importance of Ser-727 in the recruitment of transcriptional coactivators by STAT proteins. These findings reveal a novel mechanism for BRCA1 function in the IFN-γ-dependent tumor surveillance system.

Footnotes

↵ * To whom reprint requests should be addressed. E-mail: touchi{at}smtplink.mssm.edu.
This paper was submitted directly (Track II) to the PNAS office.
Article published online before print: Proc. Natl. Acad. Sci. USA, 10.1073/pnas.080469697.
Article and publication date are at www.pnas.org/cgi/doi/10.1073/pnas.080469697
Abbreviations:

STAT,

signal transducers and activators of transcription;

GST,

glutathione S-transferase;

RT-PCR,

reverse transcription–PCR;

GAL4DBD,

GAL4 DNA-binding domain;

BRCT,

BRCA1 C terminus