Research Article Open Access

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

Christian Schmidt1, Dongkyoon Kim2, Shawn Mathur2, David Covarrubias2, Chhaya Das2, Mark A. Brown3, Joachim Storsberg1 and Haley O. Tucker2
  • 1 Fraunhofer-Institute for Applied Polymer Research (IAP), Germany
  • 2 University of Texas at Austin, United States
  • 3 Colorado State University, United States

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.

American Journal of Immunology
Volume 13 No. 4, 2017, 216-232

DOI: https://doi.org/10.3844/ajisp.2017.216.232

Submitted On: 24 September 2017 Published On: 4 November 2017

How to Cite: Schmidt, C., Kim, D., Mathur, S., Covarrubias, D., Das, C., Brown, M. A., Storsberg, J. & Tucker, H. O. (2017). The Arid3a Transcription Factor Rescues Natural and RAS-V12-Induced Senescence Via a Rb-Dependent Pathway. American Journal of Immunology, 13(4), 216-232. https://doi.org/10.3844/ajisp.2017.216.232

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Keywords

  • Arid3a
  • Ras
  • Senescence
  • Immortalization