Gerald Crabtree

From Wikipedia, the free encyclopedia
Jump to navigation Jump to search
Gerald R. Crabtree
BornDecember 18, 1946
NationalityAmerican
Alma materWest Liberty State College, Temple University
Scientific career
FieldsDevelopmental Biology
InstitutionsStanford University

Gerald R. Crabtree is the David Korn Professor at Stanford University and an Investigator in the Howard Hughes Medical Institute. He is known for defining the Ca2+-calcineurin-NFAT signaling pathway, pioneering the development of synthetic ligands for regulation of biologic processes and discovering chromatin regulatory mechanisms involved in cancer and brain development. He is a founder of Ariad Pharmaceuticals, Amplyx Pharmaceuticals, and Foghorn Therapeutics.

Education and training[edit]

Crabtree grew up near Wellsburg, West Virginia, earned his B.S. in Chemistry and Mathematics from West Liberty State College and his M.D. from Temple University. While at medical school, he became interested in laboratory research and started to work at Dartmouth College with Allan Munck on the biochemistry of steroid hormones.

Key discoveries 80's and 90's[edit]

In the early 80’s Crabtree worked with Albert J. Fornace Jr. to use early bioinformatics approaches to identify remnants of transposition events (rearrangements) in the human genome [1] and to discover the HNF1 transcription factor.[2] In 1982 Crabtree discovered that one gene could produce more than one protein[3] thereby demonstrating that the coding capability of the genome is larger than expected and breaking the long-held dictum: “one gene; one protein”. In the late 80’s and early 90’s Crabtree, along with Stuart Schreiber defined the Ca2+/calcineurin/ NFAT signaling pathway,[4][5][6][7][8] which carries signals from the cell surface to the nucleus to activate immune response genes. These discoveries resulted in the first understanding of the mechanism of action of the two most commonly used immunosuppressant drugs: cyclosporin and FK506.[9] Crabtree and Schreiber found that these drugs prevent signals originating at the cell membrane from entering the nucleus by blocking the actions of the phosphatase, calcineurin preventing the entry of the NFATc proteins into the nucleus. NFAT proteins activate a large group of genes necessary for the immune response. When these genes are not activated, as occurs with Cyclosporin or FK506 administration, transplant rejection is prevented. The elucidation of the Ca2+ - Calcineurin-NFAT signaling pathway and the discovery that it is the target of Cyclosporin and FK506 was covered in the New York Times.[10] Later his laboratory used genetic approaches in mice to show that calcineurin-NFAT signaling plays essential roles in the development of many vertebrate organ systems [11] and its dysregulation is likely to be responsible for many of the phenotypes of Down Syndrome.[12] The understanding of this signaling pathway provided one of the first biochemical bridges from the cell membrane to the nucleus. (see also: Stuart Schreiber).

In 1992, working with Calvin Kuo, then a graduate student in his laboratory, he discovered that the immunosuppressive drug, rapamycin blocked a biochemical pathway leading to protein synthesis in response to membrane cell proliferation signals.[13] This work contributed to the development of rapamycin as a therapeutic for certain human cancers and also played a role in the founding of Ariad Pharmaceuticals in Cambridge, Massachusetts.

In 1993 Crabtree and Stuart Schreiber designed and synthesized the first synthetic ligands to induce proximity of proteins within cells.[14] Crabtree generalized this approach to other types of synthetic ligands including natural molecules involved in plant signaling that have expanded the usefulness of this approach.[15] At present synthetic ligands are being used to probe the function of many signaling pathways and biologic events within cells including receptor action, G-protein activation, non-receptor tyrosine kinase activation, protein stability, apoptotic signaling, transcription, and chromatin regulation. This approach has proved useful in rapidly activating and inactivating molecules to allow one to study their function. Crabtree and colleagues Nathan Hathaway and Oli Bell have used this approach to make the first measurements of the dynamics of chromatin regulation in living cells leading to an understanding of the stability of epigenetic changes involved in cellular memory.[16][17] His development of synthetic ligands was covered in the New York Times [18] and also in Discovery Magazine in 1996.[19] Later, Ariad Pharmaceuticals developed this technology for gene therapy and Bellicum Pharmaceuticals was founded on this technology by Crabtree’s former post doctoral fellow, David Spencer.

In the early 90's Crabtree worked with Paul Khavari, now the Carl J. Herzog Professor of Medicine at Stanford University, to define the mammalian SWI/SNF or BAF complex by purifying and cloning the genes that encode its subunits.[20][21] Using biochemical and genetic approaches he discovered that the genes that encode its subunits are put together like letters in a word to give a wide variety of different biological meanings.[22] In 2009 he worked with post doctoral fellow, Andrew Yoo to discover a genetic circuitry controlling the assembly of specialized, brain-specific chromatin regulatory complexes necessary for the development of the mammalian nervous system and demonstrated that recapitulating this circuitry in mammalian cells converts human skin cells to neurons.[23][24]

Crabtree, with graduate student Cigall Kadoch (now at Harvard Medical School) completed the characterization of the subunits of BAF (mSWI/SNF) chromatin remodeling complexes, and found that these complexes contribute to the cause of over 20% of human cancers and can act as either oncogenes or tumor suppressors, potentially opening a new avenue for treatment.[25][26][27]

Selected awards[edit]

  • NIH Director’s Award, 1984
  • Warner Lambert Park Davis Award, 1986
  • Howard Hughes Investigator, 1988 to present
  • Elected to the National Academy of Sciences, 1997
  • Outstanding Inventor, Stanford University, 2004
  • Thomas Scientific Laureate in Chemistry with Stuart Schreiber, 2006
  • Stanford Faculty Mentor of the Year for 2008
  • David Korn Professorship, 2008
  • Jacob Javits Neuroscience Award, 2013

Notable students and their current affiliation[edit]

  • Jorge Plutzky, Harvard University
  • Nikki Holbrook, Yale University
  • Katharine Ullman, University of Utah
  • Albert Fornace, Georgetown University
  • Calvin Kuo, Stanford University
  • Paul Khavari, Stanford University
  • Weidong Wang, National Institutes of Health
  • Isabella Graef, Stanford University
  • Oliver Rando, University of Massachusetts
  • Paul J. Utz, Stanford University
  • C.P. Chang, Indiana University
  • Monte Winslow, Stanford University
  • Jason Gestwicki, University of California, San Francisco
  • Joe Arron, Genentech
  • Julie Lessard, University of Montreal
  • Jiang Wu, The University of Texas Southwestern Medical Center
  • Andrew Yoo, Washington University
  • Nate Hathaway, University of North Carolina
  • Oliver Bell, Research Institute of Molecular Pathology, Vienna
  • Diana Hargreaves, Salk Institute for Biological Studies
  • Emily Dykhuizen, Purdue University
  • Cigall Kadoch, Harvard University

References[edit]

  1. ^ Fornace AJ, Cummings DE, Comeau CM, Kant JA, Crabtree GR. Single copy inverted repeats associated with regional duplications in gamma fibrinogen and immunoglobulin genes. Science. 224(4645): 161-164, 1984. PMID 6322310.
  2. ^ Courtois G, Morgan JG, Campbell LA, Fourel G, Crabtree, GR. Interaction of a liver-specific nuclear factor with the fibrinogen and alpha1- antitrypsin promoters. Science. 238(4827): 688-692, 1987. PMID 3499668.
  3. ^ Kant JA, Crabtree GR. Alternative mRNA splicing patterns produce the gamma A and gamma B chains of fibrinogen. Cell. 31(1): 159-166, 1982.PMID 6896326.
  4. ^ Shaw JP, Utz PJ, Durand DB, Toole JJ, Emmel EA, Crabtree GR. Identification of a putative regulator of early T cell activation genes. Science. 241(4862): 202-205, 1988. PMID 3260404.
  5. ^ Emmel EA, Verweij CL, Durand DB, Higgins KM, Lacy E, Crabtree GR. Cyclosporin A specifically inhibits function of nuclear proteins involved in T cell activation. Science. 246(4937): 1617-1620, 1989. PMID 2595372.
  6. ^ Flanagan WM, Corthésy B, Bram RJ, Crabtree GR. Nuclear association of a T-cell transcription factor blocked by FK-506 and cyclosporin A. Nature. 352(3668): 803-807, 1991. PMID 1715516
  7. ^ Clipstone NA, Crabtree GR. Identification of calcineurin as a key signalling enzyme in T-lymphocyte activation. Nature. 357(6380): 695-697, 1992. PMID 1377362.
  8. ^ Graef IA, Mermelstein PG, Stankunas K, Neilson JR, Deisseroth K, Tsien RW, Crabtree GR. L-type calcium channels and GSK-3 regulate the activity of NF-ATc4 in hippocampal neurons. Nature. 401(6754): 703-708, 1999. PMID 10537109.
  9. ^ Schreiber SL, Crabtree, GR. The mechanism of action of cyclosporin A and FK506. Immunology Today. 4: 136-142, 1992. PMID 1374612.
  10. ^ Kolata, G. Scientists decipher mysterious process of signaling in cells. New York Times. June 1993.
  11. ^ Crabtree, GR, Olson, EN. NFAT signaling: choreographing the social lives of cells. Cell. 109: S67-79, 2002. PMID 11983154.
  12. ^ Arron JR, Winslow MM, Polleri A, Chang CP, Wu H, Gao X, Neilson JR, Chen L, Heit JJ, Kim SK, Yamasaki N, Miyakawa T, Francke U, Graef IA, Crabtree GR. NFAT dysregulation by increased dosage of DSCR1 and DYRK1A on chromosome 21. Nature. 441(7093): 595-600, 2006. PMID 16554754.
  13. ^ Kuo CJ, Chung J, Fiorentino DF, Flanagan WM, Blenis J, Crabtree GR. Rapamycin selectively inhibits interleukin-2 activation of p70 S6 kinase. Nature. 358(6381): 70-73, 1992. PMID 1614535.
  14. ^ Spencer, DM, Wandless, TJ, Schreiber, SL, Crabtree GR. Controlling signal transduction with synthetic ligands. Science. 262(5136): 1019-1024, 1993. PMID 7694365.
  15. ^ Liang FS, Ho WQ, Crabtree GR. Engineering the ABA plant stress pathway for regulation of induced proximity. Sci Signal. 4(164): rs2, 2011. PMID 21406691.
  16. ^ Hathaway NA, Bell O, Hodges C, Miller EL, Neel DS, Crabtree GR. Dynamics and Memory of Heterochromatin in Living Cells. Cell. 149(7): 1447-1460, 2012. PMID 22704655.
  17. ^ Hodges C, Crabtree GR. Dynamics of inherently bounded histone modification domains. Proc Natl Acad Sci U S A. 109(33): 13296-13301, 2012. PMID 22847427.
  18. ^ Kolata G. An oddly shaped molecule is used to switch new genes on and off. New York Times. September 1995.
  19. ^ Taubes G. Conversations in a cell. Discovery Magazine. February 1996.
  20. ^ Khavari PA, Peterson CL, Tamkun JW, Mendel DB, Crabtree GR. BRG1 contains a conserved domain of the SWI2/SNF2 family necessary for normal mitotic growth and transcription. Nature. 366(6451): 170-174, 1993. PMID 8232556.
  21. ^ Wang W, Côté J, Xue Y, Zhou S, Khavari PA, Biggar SR, Muchardt C, Kalpana GV, Goff SP, Yaniv M, Workman JL, Crabtree GR. Purification and biochemical heterogeneity of the mammalian SWI-SNF complex. EMBO J. 15(19): 5370-5382, 1996. PMID 8895581.
  22. ^ Wu JI, Lessard J, Crabtree GR. Understanding the words of chromatin regulation. Cell. 136(2): 200-206, 2009. PMID 19167321.
  23. ^ Yoo AS, Staahl BT, Chen L, Crabtree GR. MicroRNA-mediated switching of chromatin-remodelling complexes in neural development. Nature. 460(7261): 642-646, 2009. PMID 19561591.
  24. ^ Yoo AS, Sun AX, Li L, Shcheglovitov A, Portmann T, Li Y, Lee-Messer C, Dolmetsch RE, Tsien RW, Crabtree GR. MicroRNA-mediated conversion of human fibroblasts to neurons. Nature. 476(7359): 228-231, 2011. PMID 21753754.
  25. ^ Kadoch C, Hargreaves DC, Hodges C, Elias L, Ho L, Ranish J, Crabtree GR. Proteomic and bioinformatic analysis of mammalian SWI/SNF complexes identifies extensive roles in human malignancy. Nat Genet. 45(6): 592-601, 2013. PMID 23644491.
  26. ^ Kadoch C, Crabtree GR. Reversible disruption of mSWI/SNF (BAF) complexes by the SS18-SSX oncogenic fusion in synovial sarcoma. Cell. 153(1): 71-85, 2013. PMID 23540691.
  27. ^ Dykhuizen EC, Hargreaves DC, Miller EL, Cui K, Korshunov A, Kool M, Pfister S, Cho YJ, Zhao K, Crabtree GR. BAF complexes facilitate decatenation of DNA by topoisomerase IIalpha. Nature. 497(7451): 624-627, 2013. PMID 23698369.

External links[edit]