Photo of Randall W. King,  MD, PhD

Randall W. King, MD, PhD

Harvard Medical School

Harvard Medical School


randy_king@hms.harvard.edu

Randall W. King, MD, PhD

Harvard Medical School

EDUCATIONAL TITLES

  • Harry C. McKenzie Professor of Cell Biology, Cell Biology, Harvard Medical School

DF/HCC PROGRAM AFFILIATION

Research Abstract

Our laboratory studies how ubiquitin-dependent protein degradation controls cell cycle progression in normal and cancer cells. We are interested in the regulation of the Anaphase-Promoting Complex, a large multisubunit complex that targets many important mitotic regulators for destruction by the ubiquitin pathway. To study this problem, we apply biochemical reconstitution with small molecule inhibitors to dissect mechanism of action. We are also interested in how chromosome segregation is perturbed in cancer cells, and we employ long-term time lapse imaging to understand how normal cells and cancer cells cope with defects in chromosome segregation. We are also using siRNA screening approaches to identify genes that modulate the sensitivity of breast cancer cells to trastuzumab (herceptin).

Publications

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  • Lu Y, Lee BH, King RW, Finley D, Kirschner MW. Substrate degradation by the proteasome: a single-molecule kinetic analysis. Science 2015; 348:1250834. PubMed
  • King RW, Finley D. Sculpting the proteome with small molecules. Nat Chem Biol 2014; 10:870-4. PubMed
  • Sackton KL, Dimova N, Zeng X, Tian W, Zhang M, Sackton TB, Meaders J, Pfaff KL, Sigoillot F, Yu H, Luo X, King RW. Synergistic blockade of mitotic exit by two chemical inhibitors of the APC/C. Nature 2014. PubMed
  • Lim HJ, Dimova NV, Tan MK, Sigoillot FD, King RW, Shi Y. The G2/M regulator histone demethylase PHF8 is targeted for degradation by the anaphase-promoting complex containing CDC20. Mol Cell Biol 2013; 33:4166-80. PubMed
  • Lee BH, Finley D, King RW. A High-Throughput Screening Method for Identification of Inhibitors of the Deubiquitinating Enzyme USP14. Curr Protoc Chem Biol 2013; 4:311-30. PubMed
  • Krajcovic M, Johnson NB, Sun Q, Normand G, Hoover N, Yao E, Richardson AL, King RW, Cibas ES, Schnitt SJ, Brugge JS, Overholtzer M. A non-genetic route to aneuploidy in human cancers. Nat Cell Biol 2011; 13:324-30. PubMed
  • Sigoillot FD, King RW. Vigilance and validation: Keys to success in RNAi screening. ACS Chem Biol 2011; 6:47-60. PubMed
  • Zeng X, Sigoillot F, Gaur S, Choi S, Pfaff KL, Oh DC, Hathaway N, Dimova N, Cuny GD, King RW. Pharmacologic inhibition of the anaphase-promoting complex induces a spindle checkpoint-dependent mitotic arrest in the absence of spindle damage. Cancer Cell 2010; 18:382-95. PubMed
  • Lee BH, Lee MJ, Park S, Oh DC, Elsasser S, Chen PC, Gartner C, Dimova N, Hanna J, Gygi SP, Wilson SM, King RW, Finley D. Enhancement of proteasome activity by a small-molecule inhibitor of USP14. Nature 2010; 467:179-84. PubMed
  • Lee MJ, Lee BH, Hanna J, King RW, Finley D. Trimming of ubiquitin chains by proteasome-associated deubiquitinating enzymes. Mol Cell Proteomics 2010. PubMed
  • Pasick J, Berhane Y, Kehler H, Hisanaga T, Handel K, Robinson J, Ojkic D, Kibenge F, Fortin M, King R, Hamel A, Spiro D, Parmley J, Soos C, Jenkins E, Breault A, Caswell D, Davies C, Rodrigue J, McAloney K, Leighton F. Survey of influenza A viruses circulating in wild birds in Canada 2005 to 2007. Avian Dis. 2010; 54:440-5. PubMed
  • Biswas D, Ranganathan B, King R, Siddiqui N. How we do it: 'tonsillectomy mat', scored rubber sheet to fix the Draffin's rods. 2010; 267:149-50. PubMed
  • Normand G, King RW. Understanding cytokinesis failure. Adv Exp Med Biol 2010; 676:27-55. PubMed
  • Atkins MB, Bukowski RM, Escudier BJ, Figlin RA, Hudes GH, Kaelin WG, Linehan WM, McDermott DF, Mier JW, Pedrosa I, Rini BI, Signoretti S, Sosman JA, Teh BT, Wood CG, Zurita AJ, King L. Innovations and challenges in renal cancer: summary statement from the Third Cambridge Conference. Cancer 2009; 115:2247-51. PubMed
  • King RW. When 2+2=5: the origins and fates of aneuploid and tetraploid cells. Biochim Biophys Acta 2008; 1786:4-14. PubMed
  • Friedman RJ, Gutkowicz-Krusin D, Farber MJ, Warycha M, Schneider-Kels L, Papastathis N, Mihm MC Jr, Googe P, King R, Prieto VG, Kopf AW, Polsky D, Rabinovitz H, Oliviero M, Cognetta A, Rigel DS, Marghoob A, Rivers J, Johr R, Grant-Kels JM, Tsao H. The diagnostic performance of expert dermoscopists vs a computer-vision system on small-diameter melanomas. Arch Dermatol 2008; 144:476-82. PubMed
  • Peng M, Falk MJ, Haase VH, King R, Polyak E, Selak M, Yudkoff M, Hancock WW, Meade R, Saiki R, Lunceford AL, Clarke CF, L Gasser D. Primary coenzyme Q deficiency in Pdss2 mutant mice causes isolated renal disease. PLoS Genet 2008; 4:e1000061. PubMed
  • Abbasi NR, Yancovitz M, Gutkowicz-Krusin D, Panageas KS, Mihm MC, Googe P, King R, Prieto V, Osman I, Friedman RJ, Rigel DS, Kopf AW, Polsky D. Utility of lesion diameter in the clinical diagnosis of cutaneous melanoma. Arch Dermatol 2008; 144:469-74. PubMed
  • Kleijnen MF, Roelofs J, Park S, Hathaway NA, Glickman M, King RW, Finley D. Stability of the proteasome can be regulated allosterically through engagement of its proteolytic active sites. Nat Struct Mol Biol 2007; 14:1180-8. PubMed
  • Bentley AM, Normand G, Hoyt J, King RW. Distinct sequence elements of cyclin B1 promote localization to chromatin, centrosomes, and kinetochores during mitosis. Mol Biol Cell 2007; 18:4847-58. PubMed
  • Overholtzer M, Mailleux AA, Mouneimne G, Normand G, Schnitt SJ, King RW, Cibas ES, Brugge JS. A nonapoptotic cell death process, entosis, that occurs by cell-in-cell invasion. Cell 2007; 131:966-79. PubMed
  • Kirkpatrick DS, Hathaway NA, Hanna J, Elsasser S, Rush J, Finley D, King RW, Gygi SP. Quantitative analysis of in vitro ubiquitinated cyclin B1 reveals complex chain topology. Nat Cell Biol 2006; 8:700-10. PubMed
  • Stern HM, Murphey RD, Shepard JL, Amatruda JF, Straub CT, Pfaff KL, Weber G, Tallarico JA, King RW, Zon LI. Small molecules that delay S phase suppress a zebrafish bmyb mutant. Nat Chem Biol 2005; 1:366-70. PubMed
  • Shi Q, King RW. Chromosome nondisjunction yields tetraploid rather than aneuploid cells in human cell lines. Nature 2005; 437:1038-42. PubMed
  • Hathaway NA, King RW. Dissecting cell biology with chemical scalpels. Curr Opin Cell Biol 2005; 17:12-9. PubMed
  • Hoyt J, King RW. Adenoviral expression of reporter proteins for high-throughput cell-based screening. Methods Mol Biol 2005; 310:187-95. PubMed
  • Salic A, King RW. Identifying small molecule inhibitors of the ubiquitin-proteasome pathway in Xenopus egg extracts. Methods Enzymol 2005; 399:567-85. PubMed
  • Lorang J, King RW. Cytological profiling: providing more haystacks for chemists' needles. Genome Biol 2005; 6:228. PubMed
  • Tochtrop GP, King RW. Target identification strategies in chemical genetics. Comb Chem High Throughput Screen 2004; 7:677-88. PubMed
  • Verma R, Peters NR, D'Onofrio M, Tochtrop GP, Sakamoto KM, Varadan R, Zhang M, Coffino P, Fushman D, Deshaies RJ, King RW. Ubistatins inhibit proteasome-dependent degradation by binding the ubiquitin chain. Science 2004; 306:117-20. PubMed
  • Cheng D, Yadav N, King RW, Swanson MS, Weinstein EJ, Bedford MT. Small molecule regulators of protein arginine methyltransferases. J Biol Chem 2004; 279:23892-9. PubMed
  • King RW. Roughing up Smoothened: chemical modulators of hedgehog signaling. J Biol 2002; 1:8. PubMed
  • Clemons PA, Koehler AN, Wagner BK, Sprigings TG, Spring DR, King RW, Schreiber SL, Foley MA. A one-bead, one-stock solution approach to chemical genetics: part 2. Chem Biol 2002; 8:1183-95. PubMed
  • Walling LA, Peters NR, Horn EJ, King RW. New technologies for chemical genetics. J Cell Biochem Suppl 2002; Suppl 37:7-12. PubMed
  • Haggarty SJ, Mayer TU, Miyamoto DT, Fathi R, King RW, Mitchison TJ, Schreiber SL. Dissecting cellular processes using small molecules: identification of colchicine-like, taxol-like and other small molecules that perturb mitosis. Chem Biol 2000; 7:275-86. PubMed
  • King RW. Chemistry or biology: which comes first after the genome is sequenced? Chem Biol 2000; 6:R327-33. PubMed
  • Mayer TU, Kapoor TM, Haggarty SJ, King RW, Schreiber SL, Mitchison TJ. Small molecule inhibitor of mitotic spindle bipolarity identified in a phenotype-based screen. Science 1999; 286:971-4. PubMed
  • Yu H, Peters JM, King RW, Page AM, Hieter P, Kirschner MW. Identification of a cullin homology region in a subunit of the anaphase-promoting complex. Science 1998; 279:1219-22. PubMed
  • King RW, Lustig KD, Stukenberg PT, McGarry TJ, Kirschner MW. Expression cloning in the test tube. Science 1997; 277:973-4. PubMed
  • Stukenberg PT, Lustig KD, McGarry TJ, King RW, Kuang J, Kirschner MW. Systematic identification of mitotic phosphoproteins. Curr Biol 1997; 7:338-48. PubMed
  • Lustig KD, Stukenberg PT, McGarry TJ, King RW, Cryns VL, Mead PE, Zon LI, Yuan J, Kirschner MW. Small pool expression screening: identification of genes involved in cell cycle control, apoptosis, and early development. Methods Enzymol 1997; 283:83-99. PubMed
  • King RW, Deshaies RJ, Peters JM, Kirschner MW. How proteolysis drives the cell cycle. Science 1996; 274:1652-9. PubMed
  • Peters JM, King RW, H. Identification of BIME as a subunit of the anaphase-promoting complex. Science 1996; 274:1199-201. PubMed
  • King RW, Glotzer M, Kirschner MW. Mutagenic analysis of the destruction signal of mitotic cyclins and structural characterization of ubiquitinated intermediates. Mol Biol Cell 1996; 7:1343-57. PubMed
  • Yu H, King RW, Peters JM, Kirschner MW. Identification of a novel ubiquitin-conjugating enzyme involved in mitotic cyclin degradation. Curr Biol 1996; 6:455-66. PubMed
  • King RW, Peters JM, Tugendreich S, Rolfe M, Hieter P, Kirschner MW. A 20S complex containing CDC27 and CDC16 catalyzes the mitosis-specific conjugation of ubiquitin to cyclin B. Cell 1995; 81:279-88. PubMed
  • King RW, Jackson PK, Kirschner MW. Mitosis in transition. Cell 1994; 79:563-71. PubMed
  • Holloway SL, Glotzer M, King RW, Murray AW. Anaphase is initiated by proteolysis rather than by the inactivation of maturation-promoting factor. Cell 1993; 73:1393-402. PubMed
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