Cancer, Cell Cycle, Developmental Biology, Drosophila, Gene Discovery, Growth, Oncogenes, Phosphorylation, Protein Degradation, Signal Transduction, Tumor Suppressor Genes, Tumorigenesis
Multi-Disciplinary Training Areas
Cancer Biology [CAB], Developmental and Stem Cell Biology [DSCB]
AB, Princeton University
PhD, Harvard Medical School
, MGH Cancer Center/Harvard and UC Berkeley
Kimmel Scholar Award
Specific Clinical/Research Interests:
How the processes of growth and proliferation are regulated and how loss of that regulation leads to cancer, with a special emphasis on regulation by the ubiquitin pathway.
Summary of Research Studies:
My lab will combine in vitro biochemical methods and in vivo Drosophila genetic analysis to understand how the processes of growth and proliferation and regulated, and how loss of that regulation results in cancer. I am pursuing the study of two main pathways: (1) an emerging tumor suppressor pathway called the "hippo pathway" and (2) the ubiquitin pathway.
(1) The hippo pathway. Hippo is a kinase that acts in a pathway with the known tumor suppressors salvador and warts. Recently, this pathway has also been connected to the merlin/nf2 tumor suppressor gene that is mutated in Neurofibromatosis type 2. Because the hippo pathway has only recently been discovered, little is known about its regulation or targets. The mammalian homologs of hippo (Mst1 and Mst2) were originally identified as stress response kinases, and the yeast homolog is involved in the Mitotic Exit Network. I am interested identifying additional targets of the hippo and warts kinases that may, themselves, represent novel tumor suppressor genes or oncogenes. My lab has completed a biochemical screen to identify downstream targets of this pathway and we are now evaluating the role of candidate targets as important effectors of the hippo pathway's tumor suppressor role.
(2) The ubiquitin pathway. Ubiquitin (a 76 amino acid protein highly conserved from yeast to humans) serves as a tag to direct proteins to different fates, such as endocytosis or degradation. The ubiquitin pathway regulates key steps in cell cycle progression, signal transduction, and growth. Mutations in its regulators, components, and targets occur in cancer and neurodegenerative diseases. Because altering the levels of ubiquitin pathway substrates can lead to cancer, identifying additional regulators and substrates is of interest. Using in vivo Drosophila characterization, my lab has discovered that signaling through the Ras pathway is elevated when ubiquitination is impaired. It is widely accepted that Receptor Tyrosine Kinases (RTKs) are regulated by ubiquitination, and our studies now suggest that the ubiquitination of Ras itself is also important to regulate proper growth and proliferation. We are now studying the biological role of Ras ubiquitination, and we intend to identify and characterize the Ras ubiquitin ligase.
The Pfleger Laboratory
Yan H, Chin ML, Horvath EA, Kane EA, Pfleger CM. Impairing ubiquitination by mutation in Drosophila E1 promote cell autonomous and non-autonomous Ras/ERK activation in vivo. Journal of Cell Science; In Press.
Pfleger CM, Harvey KF, Yan H, Hariharan IK. Mutation of the Ubiquitin Activating Enzyme Uba1 causes tissue overgrowth in Drosophila. Fly 2007;(1): 95-105.
Mills K, Harvey KF, Daish T, Pflege CM, Hariharan IK, Kumar S. The Drosophila melanogaster Apaf-1 homologue ARK is required for most, but not all, programmed cell death. J Cell Biol 2006;(172): 809-815.
Chuang LC, XN ZH, Herrera CR, Tseng HM, Pfleger CM, Block K, Yew PR. The C-terminal domain of the Xenopus cyclin-dependent kinase inhibitor, p27Xic1, is both necessary and sufficient for phosphorylation-independent proteolysis. J Biol Chem 2005;(280): 35290-35298.
Pfleger CM, Dellale I, Buff E, Lueras P, Hariharan IK. Mutations in the Drosophila orthologs of the F-actin capping protein-and-subunits cause actin accumulation and subsequent retinal degeneration. Genetics 2005;(171): 1757-1765.
Harvey KF, Pfleger CM, Hariharan IK. The Drosophila Mst ortholog, hippo, restricts growth and cell proliferation and promotes apoptosis. Cell 2003;(114): 457-467.
Chabes AL, Pfleger CM, Kirschner MW, Thelander L. Mouse ribonucleotide reductase R2 protein: a new target for anaphase-promoting complex-Cdh1-mediated proteolysis. PNAS U S A 2003;(100): 3925-3929.
Pfleger CM, Lee E, Kirschner MW. Substrate recognition by the Cdc20 and Cdh1 components of the anaphase-promoting complex. Genes and Developm 2001;(15): 2396-2407.
Pfleger CM, Salic A, Lee E, Kirschner MW. Inhibition of Cdh1-APC by the MAD2-related protein MAD2L2: a novel mechanism for regulating Cdh1. Genes and Development 2001;(15): 1759-1764.
Pfleger CM, Kirschner MW. The KEN box: an APC recognition signal distinct from the D box targeted by Cdh1. Genes and Development 2000;(14): 655-655.
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