David F Kashatus
- AB, Princeton University
- PhD, University of North Carolina
- Assistant Professor, Microbiology, Immunology, and Cancer Biology
The Role of Mitochondrial Fusion and Fission in Tumorigenesis.
Mitochondria are often pictured in biology texts as static, individual organelles, when in reality they form highly dynamic and mobile networks constantly undergoing fusion and fission. Research in the last decade has revealed that mitochondrial fusion and fission impact nearly every aspect of mitochondrial function, from cellular metabolism, to calcium homeostasis, to the control of cell survival through apoptosis and autophagy. In addition, failure to properly maintain this dynamic mitochondrial network has been shown to play a role in a number of diseases, including Parkinson’s disease, Alzheimer’s disease, diabetes and cancer. The goals of our research are: (1) to uncover the molecular mechanisms that directly control mitochondrial dynamics, (2) to identify and characterize signaling pathways that interact with the mitochondrial dynamics machinery and (3) to determine how these interactions impact the pathology of diseases such as cancer.
1. Cell cycle regulation of mitochondrial fission: Equal distribution of mitochondria to daughter cells requires that the mitochondrial network undergo fission prior to cell division. The mitotic division of mitochondria is a highly regulated process that depends on both the mitochondrial recruitment and phosphorylation of the large GTPase Drp1. Several proteins are known to play a role in this process, including the kinases Cdk1 and Aurora A, the small GTPase RalA, and the large, multifunctional protein RalBP1. Using a combination of biochemistry, cell biology and molecular genetics we are elucidating the molecular details of how these proteins collaborate to carry out this process and exploring the consequences when the process is disrupted.
2. Pathways that regulate mitochondrial dynamics: A number of important cellular processes are accompanied by changes in the mitochondrial network, but the signaling pathways that link these processes to the mitochondrial fusion and fission machinery are not well understood. Using unbiased approaches such as large-scale proteomic and RNAi screens, as well as more targeted gain- and loss-of-function analyses, we are identifying and characterizing signaling pathways that regulate mitochondrial fusion and fission. Furthermore, using a combination of biochemistry, molecular genetics and cell biology, we investigate how these pathways interact with the core mitochondrial fusion and fission machinery, the large fission GTPase Drp1, and the fusion-mediating GTPases Mfn1, Mfn2 and Opa1.
3. Mitochondrial dynamics in cancer: Mitochondrial dynamics have been shown to be important for the cellular control of apoptosis, autophagy and metabolic function, processes that are critical regulators of tumorigenesis. As such, it is essential that we understand the molecular basis of how various oncogenic signaling pathways converge upon the fusion and fission machinery and how mitochondrial dynamics contribute to oncogenic transformation and tumorigenesis. To that end, we use xenografts of human cancer cell lines and genetically engineered mouse models to determine the role that mitochondria shaping proteins play in the initiation and maintenance of human tumors.
- Cogswell P, Kashatus D, Keifer J, Guttridge D, Reuther J, Bristow C, Roy S, Nicholson D, Baldwin A. NF-kappa B and I kappa B alpha are found in the mitochondria. Evidence for regulation of mitochondrial gene expression by NF-kappa B. The Journal of biological chemistry. 2002;278(5): 2963-8. PMID: 12433922
- Reuther-Madrid J, Kashatus D, Chen S, Li X, Westwick J, Davis R, Earp H, Wang C, Baldwin Jr A. The p65/RelA subunit of NF-kappaB suppresses the sustained, antiapoptotic activity of Jun kinase induced by tumor necrosis factor. Molecular and cellular biology. 2002;22(23): 8175-83. PMID: 12417721 | PMCID: PMC134075
- Hanson J, Hawke N, Kashatus D, Baldwin A. The nuclear factor kappaB subunits RelA/p65 and c-Rel potentiate but are not required for Ras-induced cellular transformation. Cancer research. 2004;64(20): 7248-55. PMID: 15492243
- Kashatus D, Cogswell P, Baldwin A. Expression of the Bcl-3 proto-oncogene suppresses p53 activation. Genes & development. 2005;20(2): 225-35. PMID: 16384933 | PMCID: PMC1356113
- O'Neil B, Bůzková P, Farrah H, Kashatus D, Sanoff H, Goldberg R, Baldwin A, Funkhouser W. Expression of nuclear factor-kappaB family proteins in hepatocellular carcinomas. Oncology. 2007;72(1): 97-104. PMID: 18025803
- Lim K, Ancrile B, Kashatus D, Counter C. Tumour maintenance is mediated by eNOS. Nature. 2008;452(7187): 646-9. PMID: 18344980 | PMCID: PMC2688829
- Lim K, Brady D, Kashatus D, Ancrile B, Der C, Cox A, Counter C. Aurora-A phosphorylates, activates, and relocalizes the small GTPase RalA. Molecular and cellular biology. 2009;30(2): 508-23. PMID: 19901077 | PMCID: PMC2798468
- Zipfel P, Brady D, Kashatus D, Ancrile B, Tyler D, Counter C. Ral activation promotes melanomagenesis. Oncogene. 2010;29(34): 4859-64. PMID: 20562921 | PMCID: PMC2928877
- Vignola M, Kashatus D, Taylor G, Counter C, Valdivia R. cPLA2 regulates the expression of type I interferons and intracellular immunity to Chlamydia trachomatis. The Journal of biological chemistry. 2010;285(28): 21625-35. PMID: 20452986 | PMCID: PMC2898388
- Kashatus D, Lim K, Brady D, Pershing N, Cox A, Counter C. RALA and RALBP1 regulate mitochondrial fission at mitosis. Nature cell biology. 2011;13(9): 1108-15. PMID: 21822277 | PMCID: PMC3167028
- Lampson B, Kendall S, Ancrile B, Morrison M, Shealy M, Barrientos K, Crowe M, Kashatus D, White R, Gurley S, Cardona D, Counter C. Targeting eNOS in pancreatic cancer. Cancer research. 2012;72(17): 4472-82. PMID: 22738914
- Kashatus D, Counter C. Breaking up is hard to do: RalA, mitochondrial fission and cancer. Small GTPases. 2012;2(6): 329-333. PMID: 22545232 | PMCID: PMC3337163