American Journal of Immunology

The Arid3a Transcription Factor Rescues Natural and RAS-V12-Induced Senescence Via a Rb-Dependent Pathway

Christian Schmidt, Dongkyoon Kim, Shawn Mathur, David Covarrubias, Chhaya Das, Mark A. Brown, Joachim Storsberg and Haley O. Tucker

DOI : 10.3844/ajisp.2017.216.232

American Journal of Immunology

Volume 13, Issue 4

Pages 216-232

Abstract

Primary cells are protected against oncogenic events by undergoing premature cellular senescence—an irreversible cell cycle arrest activated by mitogenic signaling as well as by overexpression of tumor suppressors, including p16INK4A, p53 and PML. In the human, downregulation of Dril1/E2F-BP1, a transcriptional regulator of E2F, promotes PML-dependent premature senescence and bypass of ant-iproliferative signaling by p19Arf/p53/p21Cip1 and p16INK4a to prevent both RasV12-induced and spontaneous senescence. The mouse ortholog, Arid3A/Bright, while highly characterized in B lymphocytes for its function in immunoglobulin transcription and hematopoiesis, had yet to be assessed for a function in growth control. That, along with the considerable sequence/exon structure diversion from its human orthologs, prompted us to evaluate Arid3a in this context. We report that reduction of Arid3a levels in B lymphocytes results in G1/S cell cycle arrest whereas overexpression of Arid3a leads to accumulation of Cyclin E, hyperphosphorylation of pRb, increased transcriptional activity of E2F1 and transformation in vivo. Arid3a associates with pRb in chromatin to release HDAC1 from the E2F1 promoter in proliferating cells. Arid3a mutants that fail to associate with pRb neither rescue senescence nor induce proliferation. Our results identify a function for Arid3 in cell cycle progression beyond its previously established role in immunoglobulin gene transcription.

Copyright

© 2017 Christian Schmidt, Dongkyoon Kim, Shawn Mathur, David Covarrubias, Chhaya Das, Mark A. Brown, Joachim Storsberg and Haley O. Tucker. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.