Overview

Regulation of cell cycle checkpoints and cell death by the RB tumor suppressor in response to oxidative stress and DNA damage.

Our work investigates the critical role played by the RB tumor suppressor (and its target genes) in sensing and managing the response to oxidative stress and DNA damage, through modulation of cell death regulators and induction of cell cycle checkpoints.

Our investigations make use of three biological systems: (1) the blood system in which we investigate the role of pRb and its downstream E2f targets in stress responses during differentiation; (2) the mammary gland in which we are exploring how non-apoptotic cell death regulates mammary epithelial development and determines the rate of tumor progression and metastasis; and, (3) the liver, in which we investigate the role of non-apoptotic cell death and regenerative proliferation in hepatocyte function, liver disease and cancer. For example, using mouse models, we are currently examining how anti-oxidants might be used to prevent myelodysplasia and progression to myeloid leukemia. We are also examining how stress-induced autophagy prevents necrosis and tumor progression in a mouse model of breast cancer. Furthermore, we have identified a role for key RB/E2F target genes in preventing oxidative damage in hepatocytes and our current work is exploiting genetically engineered mouse strains and real-time imaging in vivo to determine the role of these genes in cancer progression. In summary, we are exploiting our findings regarding basic developmental processes and stress responses in biology to address mechanisms of tumor progression and drug action in cancer.

Current Research Areas

• 1. Retinoblastoma : the tumor suppressor gene paradigm.
• 2. Regulation of Cell Cycle Checkpoints by pRB/E2F.
• 3. RB and E2f-2 in terminal red cell differentiation.
• 4. Regulation of Cell Death by pRB.
• 5. BNIP3 in autophagy, cell death and tumorigenesis.

The Macleod Lab

Standing from left to right: Ben Spike (“Spike”), Huiping Liu, Jim Knabb, Kristin Tracy, Alexandra Dirlam (“Alex”), Danielle Glick. Sitting from left to right: Kay Macleod (“the Boss”), Corbin Meacham (now in graduate school at MIT).

The Macleod lab was set up at the University of Chicago in November 2001, and is currently made up of six graduate students. The Macleod lab is found on the third floor of the “West Wing” of the new Gordon Center for Integrative Sciences, next to the labs of Ilaria Rebay and Wei Du in the Ben May Department for Cancer Research.