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The Arid3a transcription factor rescues natural and RAS-V12-induced senescence via a Rb-dependent pathway

: Schmidt, Christian; Kim, Dongkyoon; Marthur, Shawn; Covarrubias, David; Das, Chhaya; Brown, Mark A.; Storsberg, Joachim; Tucker, Haley O.

Fulltext urn:nbn:de:0011-n-4776868 (528 KByte PDF)
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Created on: 5.1.2018

American Journal of Immunology 13 (2017), No.4, pp.216-232
ISSN: 1553-619X (print)
ISSN: 1558-3775 (online)
Journal Article, Electronic Publication
Fraunhofer IAP ()

Primary cellsare protected against oncogenic events by undergoing premature cellularsenescence—an irreversible cell cycle arrest activated by mitogenic signalingas well as by overexpression of tumor suppressors, including p16INK4A, p53 andPML. In the human, downregulation of Dril1/E2F-BP1, a transcriptional regulatorof E2F, promotes PML-dependent premature senescence and bypass ofanti-proliferative signaling by p19Arf/p53/p21Cip1 and p16INK4a to prevent bothRasV12-induced and spontaneous senescence. The mouse ortholog, Arid3A/Bright,while highly characterized in B lymphocytes for its function in immunoglobulintranscription and hematopoiesis, had yet to be assessed for a function ingrowth control. That, along with the considerable sequence/exon structure diversionfrom its human orthologs, prompted us to evaluate Arid3a in this context. Wereport that reduction of Arid3a levels in B lymphocytes results in G1/S cellcycle arrest whereas overexpression of Arid3a leads to accumulation of CyclinE, hyperphosphorylation of pRb, increased transcriptional activity of E2F1 andtransformation in vivo. Arid3a associates with pRb in chromatin torelease HDAC1 from the E2F1 promoter in proliferating cells. Arid3a mutantsthat fail to associate with pRb neither rescue senescence nor induceproliferation. Our results identify a function for Arid3 in cell cycleprogression beyond its previously established role in immunoglobulin genetranscription.