The long term goal of the Larner laboratory is to develop novel radiation sensitizers to improve the cure rates of patients with high grade gliomas and prostate cancer. Cells respond to DNA damage through bona fide damage-sensing pathways which first sense the DNA damage and then transmit the damage signal through signal transduction pathways to effector proteins (including kinases and phosphatases) which ultimately activate cell cycle checkpoints thereby allowing the cells time to repair the damage prior to undergoing DNA synthesis (S phase checkpoint) or mitosis (G2/M checkpoint). We hypothesize that novel radiation sensitizers can be developed by interfering with the activation of these evolutionary conserved checkpoint pathways. A second interest of our laboratory is the relationship between androgen receptor signaling and radiation resistance.
We have had a longstanding interest in and collaboration with the Brautigan Laboratory on the role of protein phosphatases in the DNA damage response. PP6 is a Ser/Thr protein phosphatase classified as a type 2A phosphatase family member on the basis of its sequence homology to the catalytic subunit of protein phosphatase 2A (PP2A) and its sensitivity to active site inhibitors such as okadaic acid, microcystin, and calyculin. We have demonstrated previously that DNA-PK binds to both the PP6 catalytic subunit and its regulatory subunit, R1. Knockdown of PP6c resulted in reduced DNA-PK activity, impaired DNA repair, and sensitization of glioblastoma cells to irradiation, suggesting that PP6c is required for DNA-PK function. Knockdown of R1 mimicked the PP6c knockdown phenotype, indicating that R1 is necessary for activation of DNA-PK by PP6c in response to IR. We have recently mapped two distinct regions of R1, one necessary but both sufficient for binding to DNA-PK and have generated R1 knockout mice.
Our work on the androgen receptor developed out of our interest in
methoxyestradiol (2-ME) as a radiation sensitizer for prostate cancer.
The androgen receptor (AR) has a vital role in the onset and
James M. Larner, M.D.
Professor and Chair, Radiation Oncology
University of Virginia School of Medicine
Lab: Room 7121, West Complex,
PO Box 800383
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