Regulation of apoptosis by p53 and the ecdysone receptor co-activator TRR in Drosophila

Kristen Marie Riley, Thomas Jefferson University

Abstract

The tumor suppressor protein p53 is a known regulator of apoptosis following exposure to DNA damage-inducing radiation. This function is conserved in Drosophila, where p53 can induce apoptosis through up-regulation of the cell death gene reaper (rpr). The Drosophila Ecdysone receptor (ER), a receptor for the steroid hormone ecdysone, is known to regulate programmed cell death during development, also through induction of rpr. While there is much data showing that p53 activity can be influenced by steroid hormone receptors, the precise nature of any functional interaction between the two is unclear. This work shows that ER is required for induction of apoptosis in embryos following exposure to radiation. Together with p53, the ER and its co-activator methyltransferase (MTase) Trithorax-related (TRR) are essential for the strong increase in transcription of rpr and two other cell death genes, sickle and grim, showing a direct role for the steroid hormone response in this apoptotic pathway. Mechanistically, ER influences p53 function through direct methylation of p53 by its co-activator TRR. This occurs on the rpr gene, where TRR can specifically di-methylate p53 at lysine 379 after radiation treatment, and this modification is essential in vivo for induction of apoptosis. Thus, these results demonstrate a specific mechanism by which a steroid hormone receptor and p53 are involved in co-regulation of cell death following DNA damage-induced apoptosis. This new mechanism may be applicable to the previously described relationship between p53 and the estrogen receptor during cancer treatment, as the human TRR homolog (ALR) is part of an estrogen receptor co-regulator complex. ^

Subject Area

Biology, Genetics

Recommended Citation

Kristen Marie Riley, "Regulation of apoptosis by p53 and the ecdysone receptor co-activator TRR in Drosophila" (January 1, 2008). ETD Collection for Thomas Jefferson University. Paper AAI3415855.
http://jdc.jefferson.edu/dissertations/AAI3415855

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