Michael Brodsky received his B.A. in Biochemistry from the University of California, Berkeley in 1989 and received his Ph.D. from the Massachusetts Institute of Technology in 1996. From 1996 to 2001, he was a post-doctoral fellow at the University of California, Berkeley where his work was supported by the American Cancer Society and the Howard Hughes Medical Institute. In 2001, Dr. Brodsky joined the faculty of the University of Massachusetts Medical School.
Drosophila p53 and DNA Damage-Induced Apoptosis
The overall goal of the lab is to understand how animal cells coordinate cell proliferation and cell death during development. To approach this problem, we are studying the regulation of apoptosis and cell cycle arrest following DNA damage in the fruit fly Drosophila melanogaster. In normal human cells, the p53 transcription factor helps regulate DNA damage-induced apoptosis, partly explaining why p53 is the most frequently mutated gene in human cancer cells. We have shown that a knockout of Drosophila p53 completely eliminates DNA damage-induced transcription and apoptosis (see figure), demonstrating that p53 function has been conserved from insects to mammals. By studying the function of fly p53, we hope to better understand how apoptosis is regulated during normal development and during tumor development.
We are using a combination of genetics, microarrays, and informatics to identify and characterize new regulators and targets of Drosophila p53. Using Affymetrix microarrays, we have identified multiple transcriptional targets of Drosophila p53 including regulators of apoptosis such as reaper and cell-cell signaling molecules such as the Drosophila homolog of Tumor Necrosis Factor. Using genetic analysis, we have identified several genes required for DNA damage-induced apoptosis or cell cycle arrest. Characterization of these genes should provide new insights into how animal tissues respond to DNA damage. As we come to understand how p53 regulates the response to DNA damage, we will explore the mechanisms that determine why only a subset of cells exposed to DNA damage enter the apoptotic pathway and how developmental signals influence that decision.
Drosophila p53 Regulates Irradiation-Induced Apoptosis
Drosophila wing discs were treated with X-rays and stained for apoptotic cells (green dots). Damage-induced apoptosis is observed in wild type animals (A, B), but not in p53 mutant animals (C, D).
A. Wild type, untreated.
B. Wild type, + X-ray.
C. p53 mutant, untreated.
D. p53 mutant, + X-ray.
Potential Rotation Projects
We are utilizing a variety of technologies to study p53 regulation and function in Drosophila. These include genetic screens, molecular biology, fluorescence and scanning electron microscopy, tissue culture, RNAi, homologous recombination, and others. Rotation projects in this lab will be determined based on a combination of the student's and PI's interests. Possible projects are listed below:
Project 1: A genetic screen for new regulators of Drosophila p53.
Project 2: Using RNAi and homologous recombination to study regulators of p53.
Project 3: Characterization of p53 activation in Drosophila tissue culture cells by flurescence microscopy, Real-Time PCR, and RNAi.
Project 4: Genetic analysis of Drosophila p53 targets identified in microarray experiments.