Ambystoma mexicanum; Biochemistry; Biology; Chemistry; Cell Biology; Neoplasms; Pharmacology; Regeneration; Drugs, Investigational; Developmental Biology; Proteasome Endopeptidase Complex; Proteasome Inhibitors
Postnatal Development & Regeneration
Yale Combined Program in the Biological and Biomedical Sciences (BBS): Biochemistry, Biophysics and Structural Biology: Cell Cycle and Signal Transduction; Drug Design, Discovery and Mechanism
Stem Cell Center, Yale: Stem Cells and Tissue Repair
We use a combination of biochemistry, molecular biology, and bio-organic chemistry to explore different aspects of developmental and cell biology. Different projects include 1) the exploration of how biologically active compounds from nature work in order to identify new probes for cell biology as well as identify novel drug targets and 2) the development of novel small molecules to control intracellular protein homeostasis.
Extensive Research Description
We develop novel reagents, which will allow us to explore new areas in cell biology. This 'chemical genetic' approach uses biologically active natural products and de novo designed small molecules to identify critical components in intracellular processes. In the past few years, our efforts have focused on anti-angiogenic, antitumor and anti-inflammatory natural products. More recently, we have explored the use of small molecules to control intracellular protein levels, either by inhibiting their degradation or by inducing their proteolysis via the 26S proteasome. A goal of this research is to develop novel methodologies that would allow for small molecule control of the 'undruggable proteome'.
- Hines J, Gough JD, Corson TW, Crews CM. Posttranslational protein knockdown coupled to receptor tyrosine kinase activation with phosphoPROTACs. Proc Natl Acad Sci U S A. (2013), May 28; 110(22):8942-7.
- Neklesa TK, Crews CM. Chemical biology: Greasy tags for protein removal. Nature. (2012) Jul 18;487(7407):308-9.
- Holman EC, Campbell LJ, and CM Crews. Microarray analysis of microRNA expression during axolotl limb regeneration. (2012) PLoS ONE doi/10.1371/journal.pone.0041804
- Sundberg TB, Darricarrere N, Griesbach H, Slusarski DC and CM Crews. (2011) Wnt Planar Cell Polarity Signaling Disruption by Aberrant Accumulation of the MetAP-2 Substrate Rab37. Chemistry & Biology, 18(10):1300-11
- Neklesa TK, Tae H-S, Schneekloth AR, Stulberg MJ, Corson TW, Sundberg TB, Holley SA, and CM Crews. (2011) Small-molecule hydrophobic tagging-induced degradation of HaloTag fusion proteins. Nature Chemical Biology, 7(8):538-43
- Campbell LJ, Suárez-Castillo EC, Ortiz-Zuazaga H, Knapp D, Tanaka EM, CM Crews. (2011) Gene expression profile of the regeneration epithelium during axolotl limb regeneration. Developmental Dynamics. 2011 240 (7):1826-40.
- A genetic interaction network of five genes for human polycystic kidney and liver diseases defines polycystin-1 as the central determinant of cyst formation. Fedeles SV, Tian X, Gallagher AR, Mitobe M, Nishio S, Lee SH, Cai Y, Geng L, CM Crews, Somlo S (2011). A genetic interaction network of five genes for human polycystic kidney and liver diseases defines polycystin-1 as the central determinant of cyst formation.
- Crews CM. (2010) Targeting the Undruggable Proteome: The Small Molecules of My Dreams. Chemistry & Biology, 17:551-555.
- Ju R, Cirone P, Lin S, Griesbach H, Slusarski DC and CM Crews. (2010) Activation of the Planar Cell Polarity Formin DAAM1 Leads to Inhibition of Endothelial Cell Proliferation, Migration and Angiogenesis, Proc. Nat. Acad. Sci, 107(15):6906-11.
- Raina K and CM Crews. (2010) Chemical Inducers of Targeted Protein Degradation. J. Biol. Chem, 285(15):11057-60.
- Campbell, LJ and CM Crews. (2008) Wound Epidermis Formation and Function in Urodele Amphibian Limb Regeneration. Cellular and Molecular Life Sciences Jan;65(1):73-9
- Leuenroth, SJ, N Bencivenga, P Igarishi, S Somlo, CM Crews. (2008) Triptolide Reduces Cystogenesis in a Model of Autosomal Dominant Polycystic Kidney Disease. J. Am. Soc. Nephrology 19:1659-1662.
- Molineaux, C, and CM Crews. (2008) Proteasome Inhibitors in Cancer Chemotherapy, Cancer: Principles and Practice of Oncology, 8th Ed. V.T DeVita, T.S. Lawrence, S.A. Rosenberg, editors. Chapter 25., pp.486-490.
- Leuenroth, S.J., et al. (2007). Triptolide is a traditional Chinese medicine-derived inhibitor of Polycystic Kidney Disease. Proc. Natl. Acad. Sci. (USA) 104:4380-4394.
- Yeh, J.R., et al. (2006). Targeted gene disruption of Methionine Aminopeptidase 2 Results in an embryonic gastrulation defect and endothelial cell growth arrest. Proc. Natl. Acad. Sci. (USA) 103(27):10379-84.