title: BRG1 and BRM loss selectively impacts RB and P53, respectively: BRG1 and BRM have differential functionsin vivo.
abstract: The SWI/SNF complex is an important regulator of gene expression that functions by interacting with a diverse array of cellular proteins. The catalytic subunits of SWI/SNF, BRG1 and BRM, are frequently lost alone or concomitantly in a range of different cancer types. This loss abrogates SWI/SNF complex function as well as the functions of proteins that are required for SWI/SNF function, such as RB1 and TP53. Yet while both proteins are known to be dependent on SWI/SNF, we found that BRG1, but not BRM, is functionally linked to RB1, such that loss of BRG1 can directly or indirectly inactivate the RB1 pathway. This newly discovered dependence of RB1 on BRG1 is important because it explains why BRG1 loss can blunt the growth-inhibitory effect of tyrosine kinase inhibitors (TKIs). We also observed that selection forTrp53mutations occurred in Brm-positive tumors but did not occur in Brm-negative tumors. Hence, these data indicate that, during cancer development, Trp53 is functionally dependent on Brm but not Brg1. Our findings show for the first time the key differences in Brm- and Brg1-specific SWI/SNF complexes and help explain why concomitant loss of Brg1 and Brm frequently occurs in cancer, as well as how their loss impacts cancer development.
authors.affiliation: Department of Hematology/Oncology, Medicine, University of Florida, Gainesville, FL, USA.
authors.forename: Stefanie B
authors.initials: SB
authors.lastname: Marquez-Vilendrer
authors.affiliation: Department of Hematology/Oncology, Medicine, University of Florida, Gainesville, FL, USA.
authors.forename: Sudhir K
authors.initials: SK
authors.lastname: Rai
authors.affiliation: Department of Hematology/Oncology, Medicine, University of Florida, Gainesville, FL, USA.
authors.forename: Sarah Jb
authors.initials: SJ
authors.lastname: Gramling
authors.affiliation: Department of Hematology/Oncology, Medicine, University of Florida, Gainesville, FL, USA; Department of Pathology, University of Florida, Gainesville, FL, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Lu
authors.affiliation: Department of Hematology/Oncology, Medicine, University of Florida, Gainesville, FL, USA.
authors.forename: David N
authors.initials: DN
authors.lastname: Reisman
keywords: lung cancer; p53; retinoblastoma; swi/snf; tumor suppressor