Overview

Work in the Macleod lab focuses on understanding the role of oxidative stress in cell growth, differentiation and tumor progression.

Our work investigates how the cell senses and manages responses to oxidative stress through induction of cell cycle checkpoints, modulation of cell death regulators and changes in cellular metabolism and relates this to defective stress responses in tumor cells.

Our investigations make use of three biological systems: (1) the blood system in which we investigate the role of the RB tumor suppressor and its downstream E2f targets in responses to oxidative stress, including how stem cells respond to ROS and how this influences the etiology of hematopoietic malignancies; (2) the mammary gland in which we are exploring how autophagy and 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 autophagy and fatty acid metabolism 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.