DF/HCC Program Affiliation

Breast Cancer
Cancer Cell Biology

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

• 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 Jul;8(7):700-10.
  16799550
• Shi Q, King RW.Chromosome nondisjunction yields tetraploid rather than aneuploid cells in human cell lines.Nature 2005 Oct 13;437(7061):1038-42.
  16222248
• 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 Oct 1;306(5693):117-20.
  15459393
• 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 Apr;4(4):e1000061.
  18437205
• 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 diag
  18427041
• 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 Apr;144(4):469-74.
  18427040
• 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 Nov 30;131(5):966-79.
  18045538
• 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 Dec;14(12):1180-8.
  18026118
• 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 Dec;18(12):4847-58.
  17881737
• 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 Dec;1(7):366-70.
  16372403
• Hoyt J, King RW.Adenoviral expression of reporter proteins for high-throughput cell-based screening.Methods Mol Biol 2005;310:187-95.
  16353377
• Salic A, King RW.Identifying small molecule inhibitors of the ubiquitin-proteasome pathway in Xenopus egg extracts.Methods Enzymol 2005;399:567-85.
  16338382
• Lorang J, King RW.Cytological profiling: providing more haystacks for chemists' needles.Genome Biol 2005;6(8):228.
  16086858
• Hathaway NA, King RW.Dissecting cell biology with chemical scalpels.Curr Opin Cell Biol 2005 Feb;17(1):12-9.
  15661514
• Tochtrop GP, King RW.Target identification strategies in chemical genetics.Comb Chem High Throughput Screen 2004 Nov;7(7):677-88.
  15578930
• Cheng D, Yadav N, King RW, Swanson MS, Weinstein EJ, Bedford MT.Small molecule regulators of protein arginine methyltransferases.J Biol Chem 2004 Jun 4;279(23):23892-9.
  15056663
• King RW.Roughing up Smoothened: chemical modulators of hedgehog signaling.J Biol 2002 Nov 6;1(2):8.
  12437769
• Walling LA, Peters NR, Horn EJ, King RW.New technologies for chemical genetics.J Cell Biochem Suppl 2001;Suppl 37:7-12.
  11842422
• 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 2001 Dec;8(12):1183-95.
  11755397
• 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 Apr;7(4):275-
  10780927
• King RW.Chemistry or biology: which comes first after the genome is sequenced?.Chem Biol 1999 Dec;6(12):R327-33.
  10631509
• 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 Oct 29;286(5441):971-4.
  10542155
• 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 Feb 20;279(5354):1219-22.
  9469815
• King RW, Lustig KD, Stukenberg PT, McGarry TJ, Kirschner MW.Expression cloning in the test tube.Science 1997 Aug 15;277(5328):973-4.
  9281074
• Stukenberg PT, Lustig KD, McGarry TJ, King RW, Kuang J, Kirschner MW.Systematic identification of mitotic phosphoproteins.Curr Biol 1997 May 1;7(5):338-48.
  9115395
• 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.
  9251013
• King RW, Deshaies RJ, Peters JM, Kirschner MW.How proteolysis drives the cell cycle.Science 1996 Dec 6;274(5293):1652-9.
  8939846
• Peters JM, King RW, Höög C, Kirschner MW.Identification of BIME as a subunit of the anaphase-promoting complex.Science 1996 Nov 15;274(5290):1199-201.
  8895470
• 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 Sep;7(9):1343-57.
  8885231
• Yu H, King RW, Peters JM, Kirschner MW.Identification of a novel ubiquitin-conjugating enzyme involved in mitotic cyclin degradation.Curr Biol 1996 Apr 1;6(4):455-66.
  8723350
• 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 Apr 21;81(2):279-88.
  7736580
• King RW, Jackson PK, Kirschner MW.Mitosis in transition.Cell 1994 Nov 18;79(4):563-71.
  7954823
• Holloway SL, Glotzer M, King RW, Murray AW.Anaphase is initiated by proteolysis rather than by the inactivation of maturation-promoting factor.Cell 1993 Jul 2;73(7):1393-402.
  8391932