Hutchinson, John - Date Last Updated: 05/14/2009

John Hutchinson - Email
PhD Candidate - Started 2007
Sparta, WI
Lab of Randall Tibbetts, PhD

Undergraduate Work
University of Wisconsin-Madison (2002-2006)
Bachelors of Science-Biology (2006)

Research as of Spring 2009
The cAMP response element binding protein (CREB) is a transcription factor implicated in the regulation of genes involved in a wide array of functions including metabolism, cell survival, DNA repair, learning and memory. CREB is phosphorylated by more than 20 kinases on many different residues and the phosphorylation status of CREB affects its activity. CREB activity is enhanced by stimuli, including cAMP and Ca2+, that induce phosphorylation on Ser-133, located in the kinase inducible domain (KID). In addition to the canonical Ser-133-dependent CREB activation, phosphorylation at other residues within the KID have shown to be both stimulatory and inhibitory.

Previous work from our laboratory has shown that CREB is a target of the DNA damage response. A cluster of evolutionarily conserved serines within the KID are phosphorylated in response to DNA damaging stimuli such as ionizing radiation, chemotherapeutic agents, and a number of DNA-damaging environmental toxicants. These phosphorylation sites are collectively referred to as the coregulated ATM and casein kinase sites (RAX) domain.

In response to DNA damage, ATM phosphorylates CREB on Ser-111. This triggers the processive phosphorylation on Serines 108, 114, and 117 by casein kinase 1 (CK1) and casein kinase 2 (CK2). Phosphorylation at these sites allows ATM to phosphorylate Ser-121. We hypothesize that phosphorylation of the RAX domain inhibits the transactivation potential of CREB by destabilizing CREB's interaction with the transcriptional coactivator, CREB binding protein (CBP).

Aside from the DNA damage-dependent pathway, we have observed that phosphorylation of the CREB RAX domain also occurs in the absence of DNA damage in multiple cell types, including HEK 293T, K562, HeLa, and C2C12 cells. The focus of my research is to elucidate the signaling events leading to DNA damage independent RAX domain phosphorylation and to understand how this reponse is modulated by exposure to environmental toxicants. The proposed research will improve our understanding of the mechanisms of CREB regulation in response to environmental agents and may reveal novel signaling paradigms.

Date Last Updated: 05/14/2009 webteam@med.wisc.edu