Kay F Macleod

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.

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,...

Kay F. Macleod: Functions of the retinoblastoma tumor suppressor in modulating oxidative stress responses in the hematopoietic system. Nature Reviews in Cancer 8, 769-81(2008) 

Dirlam, A. Spike, B.T. & Macleod, KF: De-regulated E2f-2 activity drives deregulated cell cycle and maturation defects in Rb null erythroblasts. Mol.Cell Biol. 27 (24) 8713-28 (2007). 

Kristin Tracy, Benjamin C. Dibling, Benjamin T. Spike, James Knabb, Paul Schumacker & Macleod KF: BNIP3 is an RB/E2F target gene required for hypoxia-induced autophagy. Mol. Cell Biol. 27, 6229-42 (2007). 

Spike, BT, Dibling BC & Macleod, KF: Hypoxic stress underlies defects in erythroblast islands in the Rb null mouse. Blood 110, 2173-81 (2007). 

Abhinav Diwan, Andrew G Koesters, Amy M Odley, Suvarnamala Pushkaran, Christopher P Baines, Benjamin T Spike, Diedre Daria, Anil G Jegga, Hartmut Geiger, Bruce J Aronow, Jeffrey D Molkentin, Kay F Macleod, Theodosia A Kalfa, Gerald W Dorn II: Unrestrained erythroblast development in Nix-/- mice reveals a mechanism for apoptotic modulation of erythropoiesis. Proc.Natl.Acad.Sci. USA 104, 6794-9 (2007). 

Kristin Tracy & Kay F. Macleod: Regulation of mitochondrial integrity, autophagy and cell survival by BNIP3. In press at Autophagy 3, (6) 616-619(2007). 

Tamara Lotan, Jonathan Hickson, Jeffery Souris, Dehzeng Huo, Jennifer Taylor, Terry Li, Kristen Otto, Seiko Diane Yamada, Kay Macleod & Carrie W. Rinker-Schaeffer: MKK4 Suppresses Metastatic Colonization in Ovarian Cancer through Cellular Growth Arrest Associated Upregulation of p21. Cancer Research 68, 2166-75 (2008). 

Benjamin T Spike & Kay F. Macleod: Effects of hypoxia on heterotypic interactions with macrophages. Cell Cycle 6, (21) 2620-24(2007). 

Spike, BT, Dirlam, A, Dibling, BC, Marvin, J, Williams, BO, Jacks, T & KF Macleod The Rb tumor suppressor is required for stress erythropoiesis. The EMBO Journal. 23: 4319-29 (2004). 

Spike, BT & KF Macleod The Rb tumor suppressor in stress responses and hematopoietic homeostasis. Cell Cycle 4: e181-184 (2005). 

Liu, H., Dibling, B., Spike B, Dirlam, A & Macleod, K: Novel functions of the RB tumor suppressor. Curr. Op. Gen. & Dev. 14, 55-64 (2004). 

Liu H, Thompson AM & KF Macleod: A novel form of pRb expressed during normal myelopoiesis and in tumor associated macrophages. Cell Proliferation 38: 13-24 (2005). 

Dirlam A. & KF Macleod :The Retinoblastoma tumour suppressor. The Cancer Handbook. 2nd Edition. Chapter 24. Edited by Malcolm R Alison. John Wiley & Sons Ltd. (2006). 

Kay F. Macleod: Functions of the retinoblastoma tumor suppressor in modulating oxidative stress responses in the hematopoietic system. Nature Reviews in Cancer 8, 769-81(2008) 

Dirlam, A. Spike, B.T. & Macleod, KF: De-regulated E2f-2 activity drives deregulated cell cycle and maturation defects in Rb null erythroblasts. Mol.Cell Biol. 27 (24) 8713-28 (2007). 

Kristin Tracy, Benjamin C. Dibling, Benjamin T. Spike, James Knabb, Paul Schumacker & Macleod KF: BNIP3 is an RB/E2F target gene required for hypoxia-induced autophagy. Mol. Cell Biol. 27, 6229-42 (2007). 

Spike, BT, Dibling BC & Macleod, KF: Hypoxic stress underlies defects in erythroblast islands in the Rb null mouse. Blood 110, 2173-81 (2007). 

Abhinav Diwan, Andrew G Koesters, Amy M Odley, Suvarnamala Pushkaran, Christopher P Baines, Benjamin T Spike, Diedre Daria, Anil G Jegga, Hartmut Geiger, Bruce J Aronow, Jeffrey D Molkentin, Kay F Macleod, Theodosia A Kalfa, Gerald W Dorn II: Unrestrained erythroblast development in Nix-/- mice reveals a mechanism for apoptotic modulation of erythropoiesis. Proc.Natl.Acad.Sci. USA 104, 6794-9 (2007).