The Interplay between Bag-1 and STAT-1 in regulating cell death - cancer to cardioprotection

Monday 13 February 2012, 1.15PM

Speaker: Professor Paul Townsend, University of Southampton

Host: James Chong

Abstract:

Bag-1, a multifunctional pro-survival protein, can regulate the pivotal role of the STAT-1 transcription factor in mediating cellular stress in cells. We have previously demonstrated a significant role for Bag-1 in breast and blood borne cancer cell survival, especially following toxic challenge. However, these observations are in cells that are clearly proliferative and highly so. Here we show data following patho-physiological challenge of ischemia reperfusion induced apoptosis in terminally differentiated cardiac myocytes; an ex vivo model akin to mimicking a heart attack. Our data show that the cytoplasmic short isoform of Bag-1 (Bag-1S) is responsible for providing cardioprotection and its overexpression promotes cardiac myocyte survival following stress. Molecular interrogation further shows that STAT-1 interacts with Bag-1S but not the long Bag-1 isoform (Bag-1L), an association which is enhanced following exposure to ischemia/reperfusion injury and other stresses. Furthermore, co-immunoprecipitation suggests that this STA-1:bag-1 axis occurs through the conserved “Bag” domain. On binding to STAT-1, Bag-1 dramatically reduces the levels of apoptosis mediated through STAT-1 without altering expression of total STAT-1 protein. Subcellular fractionation implies that Bag-1 retains STAT-1 within the nucleus. Furthermore, overexpression of Bag-1 represses STAT-1 activation as shown by a decrease in phospho-STAT-1701 and attenuates the pro-death activity of STAT-1 through a reduction in STAT-1 responsive transcriptional targets fas, caspase-1, p53, noxa and bax. Together these data reveal that Bag-1 plays a crucial role in modulating STAT-1 pro-death activity following cellular stress, in the heart - thus demonstrating a novel functional regulation of STAT-1 by Bag-1 and a possible interface for therapeutic intervention.

Location: Biology Lecture Theatre (K018)

Email: cii@york.ac.uk

Telephone: 01904 328875