Open AccessBRD4 Short Isoform Interacts with RRP1B, SIPA1 and Components of the LINC Complex at the Inner Face of the Nuclear Membrane
Author(s) -
Jude Alsarraj,
Farhoud Faraji,
Thomas Geiger,
Katherine Mattaini,
Mia Williams,
Josephine J. Wu,
Ngoc-Han Ha,
Tyler Merlino,
Renard C. Walker,
Allen D. Bosley,
Zhen Xiao,
Þorkell Andrésson,
Dominic Esposito,
Nicholas Smithers,
Dave Lugo,
Rab K. Prinjha,
Anup Day,
Nigel P.S. Crawford,
Keiko Ozato,
Kevin Gardner,
Kent W. Hunter
Publication year - 2013
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0080746
Subject(s) - gene isoform , brd4 , histone , bromodomain , biology , nuclear localization sequence , nuclear transport , microbiology and biotechnology , nuclear protein , inner membrane , cancer research , transcription factor , cell nucleus , biochemistry , gene , nucleus , mitochondrion
Recent studies suggest that BET inhibitors are effective anti-cancer therapeutics. Here we show that BET inhibitors are effective against murine primary mammary tumors, but not pulmonary metastases. BRD4 , a target of BET inhibitors, encodes two isoforms with opposite effects on tumor progression. To gain insights into why BET inhibition was ineffective against metastases the pro-metastatic short isoform of BRD4 was characterized using mass spectrometry and cellular fractionation. Our data show that the pro-metastatic short isoform interacts with the LINC complex and the metastasis-associated proteins RRP1B and SIPA1 at the inner face of the nuclear membrane. Furthermore, histone binding arrays revealed that the short isoform has a broader acetylated histone binding pattern relative to the long isoform. These differential biochemical and nuclear localization properties revealed in our study provide novel insights into the opposing roles of BRD4 isoforms in metastatic breast cancer progression.