The ATPase-powered SWI/SNF chromatin remodeling complex plays an essential role in the regulation of gene expression during development and differentiation in essentially all tissues. The complex consists of eight or more associated proteins, and is part of the mechanism that regulates activator and repressor access to individual genes. Deficiency of any of several components of the complex is linked with tumor susceptibility. Deficiency of the ATPase itself is linked with carcinogenesis in several tissue types. The noncatalytic subunits can also be essential for the anti-proliferative role of the complex, and the noncatalytic subunit INI1/ hSNF5 is already recognized as a human tumor susceptibility gene. Germ-line mutations in INI1 have been identified, and carriers are pre-disposed in childhood to malignant rhabdoid tumors and tumors of the central nervous system. These tumors are consistent with a vital role for the complex in terminal differentiation and differentiation-associated cell cycle arrest. The full complement of noncatalytic subunits is expressed in most cells, but the specific range of tumors linked with INI1 deficiency suggests that individual subunits may be more important for control of differentiation and proliferation in some tissue types than in others. The largest subunit in the complex, the 270kDa protein product of the ARID1A gene, is present in the complex as one of two alternative, closely related, independently encoded proteins. We have recently found that the presence of the p270/ARID1A subunit instead of the alternative ARID1B subunit defines a complex with an anti-proliferative function during terminal differentiation. Using an osteoblast differentiation cell culture model we found that cells depleted of p270 by expression of an appropriate siRNA fail to undergo normal differentiation-associated cell cycle arrest even though the SWI/SNF complexes remain otherwise intact. This implies that deficiency of p270/ARID1A would increase the tumorigenic potential of cells. The forms of cancer to which deficiency of p270 might increase susceptibility are presently unknown. However, several intriguing lines of information suggest that p270, in its role within the SWI/SNF complex, may be critical to the proliferation-regulating functions of differentiating nephroblasts, the cells that give rise to the pediatric kidney cancer known as Wilms' tumor. Our hypothesis is that deficiency of p270/ARID1A is functionally similar to loss of Wilms' tumor susceptibility gene 1 (WT1), and that ARID1A itself is a susceptibility gene for Wilms' tumor. We are requesting preliminary support to explore this new idea with the expectation of developing it to the point that its study will merit R01 support. ? ? ?
