DF/HCC Program Affiliation

Cancer Cell Biology

Research Abstract

My work is focused on understanding how the cell division cycle is controlled. We study the regulation of cyclin-dependent kinases and their inhibitors as well as other signalling pathways controlled by protein kinases. Much of this regulation occurs through protein turnover through the ubiquitin pathway. My lab is interested in the control of protein turnover through the SCF ubiquitin ligases. In recent years, we have identified ubiquitin ligases for I-kappa B, beta-catenin, cyclin E, and Cdc25, key regulators of cell division and survival. Currently, genomic and biochemical approaches are being used to dissect how that activities of these and other processes are controlled.

Publications

• Stegmeier F, Rape M, Draviam VM, Nalepa G, Sowa ME, Ang XL, McDonald ER, Li MZ, Hannon GJ, Sorger PK, Kirschner MW, Harper JW, Elledge SJ.Anaphase initiation is regulated by antagonistic ubiquitination and deubiquitination activities.Nature 2007 Apr 19;44
  17443180
• Draviam VM, Stegmeier F, Nalepa G, Sowa ME, Chen J, Liang A, Hannon GJ, Sorger PK, Harper JW, Elledge SJ.A functional genomic screen identifies a role for TAO1 kinase in spindle-checkpoint signalling.Nat Cell Biol 2007 May;9(5):556-64.
  17417629
• Sundqvist A, Bengoechea-Alonso MT, Ye X, Lukiyanchuk V, Jin J, Harper JW, Ericsson J.Control of lipid metabolism by phosphorylation-dependent degradation of the SREBP family of transcription factors by SCF(Fbw7).Cell Metab 2005 Jun;1(6):379-91.
  16054087
• Wei W, Jin J, Schlisio S, Harper JW, Kaelin WG.The v-Jun point mutation allows c-Jun to escape GSK3-dependent recognition and destruction by the Fbw7 ubiquitin ligase.Cancer Cell 2005 Jul;8(1):25-33.
  16023596
• Jin J, Shirogane T, Xu L, Nalepa G, Qin J, Elledge SJ, Harper JW.SCFbeta-TRCP links Chk1 signaling to degradation of the Cdc25A protein phosphatase.Genes Dev 2003 Dec 15;17(24):3062-74.
  14681206
• Ye X, Wei Y, Nalepa G, Harper JW.The cyclin E/Cdk2 substrate p220(NPAT) is required for S-phase entry, histone gene expression, and Cajal body maintenance in human somatic cells.Mol Cell Biol 2003 Dec;23(23):8586-600.
  14612403
• Xu L, Wei Y, Reboul J, Vaglio P, Shin TH, Vidal M, Elledge SJ, Harper JW.BTB proteins are substrate-specific adaptors in an SCF-like modular ubiquitin ligase containing CUL-3.Nature 2003 Sep 18;425(6955):316-21.
  13679922
• Wu G, Xu G, Schulman BA, Jeffrey PD, Harper JW, Pavletich NP.Structure of a beta-TrCP1-Skp1-beta-catenin complex: destruction motif binding and lysine specificity of the SCF(beta-TrCP1) ubiquitin ligase.Mol Cell 2003 Jun;11(6):1445-56.
  12820959
• Wang Y, Shirogane T, Liu D, Harper JW, Elledge SJ.Exit from exit: resetting the cell cycle through Amn1 inhibition of G protein signaling.Cell 2003 Mar 7;112(5):697-709.
  12628189
• Kato N, Sakata T, Breton G, Le Roch KG, Nagle A, Andersen C, Bursulaya B, Henson K, Johnson J, Kumar KA, Marr F, Mason D, McNamara C, Plouffe D, Ramachandran V, Spooner M, Tuntland T, Zhou Y, Peters EC, Chatterjee A, Schultz PG, Ward GE, Gray N, Harper J,
  18454143
• Westbrook TF, Hu G, Ang XL, Mulligan P, Pavlova NN, Liang A, Leng Y, Maehr R, Shi Y, Harper JW, Elledge SJ.SCFbeta-TRCP controls oncogenic transformation and neural differentiation through REST degradation.Nature 2008 Mar 20;452(7185):370-4.
  18354483
• Schlabach MR, Luo J, Solimini NL, Hu G, Xu Q, Li MZ, Zhao Z, Smogorzewska A, Sowa ME, Ang XL, Westbrook TF, Liang AC, Chang K, Hackett JA, Harper JW, Hannon GJ, Elledge SJ.Cancer proliferation gene discovery through functional genomics.Science 2008 Feb 1;
  18239126
• Bennett EJ, Harper JW.DNA damage: ubiquitin marks the spot.Nat Struct Mol Biol 2008 Jan;15(1):20-2.
  18176551
• Harper JW, Elledge SJ.The DNA damage response: ten years after.Mol Cell 2007 Dec 14;28(5):739-45.
  18082599
• Huh K, Zhou X, Hayakawa H, Cho JY, Libermann TA, Jin J, Wade Harper J, Munger K.Human papillomavirus type 16 e7 oncoprotein associates with the cullin 2 ubiquitin ligase complex, which contributes to degradation of the retinoblastoma tumor suppressor.J Vi
  17609271
• Jin J, Li X, Gygi SP, Harper JW.Dual E1 activation systems for ubiquitin differentially regulate E2 enzyme charging.Nature 2007 Jun 28;447(7148):1135-8.
  17597759
• Ghule PN, Becker KA, Harper JW, Lian JB, Stein JL, van Wijnen AJ, Stein GS.Cell cycle dependent phosphorylation and subnuclear organization of the histone gene regulator p220(NPAT) in human embryonic stem cells.J Cell Physiol 2007 Oct;213(1):9-17.
  17520687
• Harper JW, Schulman BA.Structural complexity in ubiquitin recognition.Cell 2006 Mar 24;124(6):1133-6.
  16564007
• Lee TH, Perrem K, Harper JW, Lu KP, Zhou XZ.The F-box protein FBX4 targets PIN2/TRF1 for ubiquitin-mediated degradation and regulates telomere maintenance.J Biol Chem 2006 Jan 13;281(2):759-68.
  16275645
• Miele A, Braastad CD, Holmes WF, Mitra P, Medina R, Xie R, Zaidi SK, Ye X, Wei Y, Harper JW, van Wijnen AJ, Stein JL, Stein GS.HiNF-P directly links the cyclin E/CDK2/p220NPAT pathway to histone H4 gene regulation at the G1/S phase cell cycle transition.M
  15988025
• Shirogane T, Jin J, Ang XL, Harper JW.SCFbeta-TRCP controls clock-dependent transcription via casein kinase 1-dependent degradation of the mammalian period-1 (Per1) protein.J Biol Chem 2005 Jul 22;280(29):26863-72.
  15917222
• Jin J, Cardozo T, Lovering RC, Elledge SJ, Pagano M, Harper JW.Systematic analysis and nomenclature of mammalian F-box proteins.Genes Dev 2004 Nov 1;18(21):2573-80.
  15520277
• Cullinan SB, Gordan JD, Jin J, Harper JW, Diehl JA.The Keap1-BTB protein is an adaptor that bridges Nrf2 to a Cul3-based E3 ligase: oxidative stress sensing by a Cul3-Keap1 ligase.Mol Cell Biol 2004 Oct;24(19):8477-86.
  15367669
• Ye X, Nalepa G, Welcker M, Kessler BM, Spooner E, Qin J, Elledge SJ, Clurman BE, Harper JW.Recognition of phosphodegron motifs in human cyclin E by the SCF(Fbw7) ubiquitin ligase.J Biol Chem 2004 Nov 26;279(48):50110-9.
  15364936
• Nalepa G, Harper JW.Visualization of a highly organized intranuclear network of filaments in living mammalian cells.Cell Motil Cytoskeleton 2004 Oct;59(2):94-108.
  15362113
• Ang XL, Harper JW.Interwoven ubiquitination oscillators and control of cell cycle transitions.Sci STKE 2004 Jul 20;2004(242):pe31.
  15266102
• Harper JW.Neddylating the guardian; Mdm2 catalyzed conjugation of Nedd8 to p53.Cell 2004 Jul 9;118(1):2-4.
  15242638
• Welcker M, Orian A, Jin J, Grim JA, Harper JW, Eisenman RN, Clurman BE.The Fbw7 tumor suppressor regulates glycogen synthase kinase 3 phosphorylation-dependent c-Myc protein degradation.Proc Natl Acad Sci U S A 2004 Jun 15;101(24):9085-90.
  15150404
• Tetzlaff MT, Bai C, Finegold M, Wilson J, Harper JW, Mahon KA, Elledge SJ.Cyclin F disruption compromises placental development and affects normal cell cycle execution.Mol Cell Biol 2004 Mar;24(6):2487-98.
  14993286
• Tetzlaff MT, Yu W, Li M, Zhang P, Finegold M, Mahon K, Harper JW, Schwartz RJ, Elledge SJ.Inaugural Article, From The Cover: Defective cardiovascular development and elevated cyclin E and Notch proteins in mice lacking the Fbw7 F-box protein.Proc Natl Aca
  14766969
• Li S, Armstrong CM, Bertin N, Ge H, Milstein S, Boxem M, Vidalain PO, Han JD, Chesneau A, Hao T, Goldberg DS, Li N, Martinez M, Rual JF, Lamesch P, Xu L, Tewari M, Wong SL, Zhang LV, Berriz GF, Jacotot L, Vaglio P, Reboul J, Hirozane-Kishikawa T, Li Q, Ga
  14704431
• Rodriguez M, Li SS, Harper JW, Songyang Z.An oriented peptide array library (OPAL) strategy to study protein-protein interactions.J Biol Chem 2004 Mar 5;279(10):8802-7.
  14679191
• Wang W, Ungermannova D, Jin J, Harper JW, Liu X.Negative regulation of SCFSkp2 ubiquitin ligase by TGF-beta signaling.Oncogene 2004 Feb 5;23(5):1064-75.
  14676846
• Mitra P, Xie RL, Medina R, Hovhannisyan H, Zaidi SK, Wei Y, Harper JW, Stein JL, van Wijnen AJ, Stein GS.Identification of HiNF-P, a key activator of cell cycle-controlled histone H4 genes at the onset of S phase.Mol Cell Biol 2003 Nov;23(22):8110-23.
  14585971
• Jin J, Harper JW.A license to kill: transcriptional activation and enhanced turnover of Myc by the SCF(kp2) ubiquitin ligase.Cancer Cell 2003 Jun;3(6):517-8.
  12842079
• Baumgartner B, Harper JW.Deafening cycle.Nat Cell Biol 2003 May;5(5):385-7.
  12724771
• Wei Y, Jin J, Harper JW.The cyclin E/Cdk2 substrate and Cajal body component p220(NPAT) activates histone transcription through a novel LisH-like domain.Mol Cell Biol 2003 May;23(10):3669-80.
  12724424
• Passmore LA, McCormack EA, Au SW, Paul A, Willison KR, Harper JW, Barford D.Doc1 mediates the activity of the anaphase-promoting complex by contributing to substrate recognition.EMBO J 2003 Feb 17;22(4):786-96.
  12574115
• Yang G, Ayala G, De Marzo A, Tian W, Frolov A, Wheeler TM, Thompson TC, Harper JW.Elevated Skp2 protein expression in human prostate cancer: association with loss of the cyclin-dependent kinase inhibitor p27 and PTEN and with reduced recurrence-free survi
  12429629
• Nelson DM, Ye X, Hall C, Santos H, Ma T, Kao GD, Yen TJ, Harper JW, Adams PD.Coupling of DNA synthesis and histone synthesis in S phase independent of cyclin/cdk2 activity.Mol Cell Biol 2002 Nov;22(21):7459-72.
  12370293
• Harper JW, Burton JL, Solomon MJ.The anaphase-promoting complex: it's not just for mitosis any more.Genes Dev 2002 Sep 1;16(17):2179-206.
  12208841
• Nalepa G, Harper JW.Efp: a ring of independence?.Nat Med 2002 Jul;8(7):661-2.
  12091896
• Jin J, Harper JW.RING finger specificity in SCF-driven protein destruction.Dev Cell 2002 Jun;2(6):685-7.
  12062077
• Zheng N, Schulman BA, Song L, Miller JJ, Jeffrey PD, Wang P, Chu C, Koepp DM, Elledge SJ, Pagano M, Conaway RC, Conaway JW, Harper JW, Pavletich NP.Structure of the Cul1-Rbx1-Skp1-F boxSkp2 SCF ubiquitin ligase complex.Nature 2002 Apr 18;416(6882):703-9.
  11961546
• Au SW, Leng X, Harper JW, Barford D.Implications for the ubiquitination reaction of the anaphase-promoting complex from the crystal structure of the Doc1/Apc10 subunit.J Mol Biol 2002 Mar 1;316(4):955-68.
  11884135
• Leng X, Noble M, Adams PD, Qin J, Harper JW.Reversal of growth suppression by p107 via direct phosphorylation by cyclin D1/cyclin-dependent kinase 4.Mol Cell Biol 2002 Apr;22(7):2242-54.
  11884610
• Harper JW.A phosphorylation-driven ubiquitination switch for cell-cycle control.Trends Cell Biol 2002 Mar;12(3):104-7.
  11859016
• Harper JW, Adams PD.Cyclin-dependent kinases.Chem Rev 2001 Aug;101(8):2511-26.
  11749386
• Koepp DM, Schaefer LK, Ye X, Keyomarsi K, Chu C, Harper JW, Elledge SJ.Phosphorylation-dependent ubiquitination of cyclin E by the SCFFbw7 ubiquitin ligase.Science 2001 Oct 5;294(5540):173-7.
  11533444
• Harper JW.Protein destruction: adapting roles for Cks proteins.Curr Biol 2001 Jun 5;11(11):R431-5.
  11516665
• Ye X, Zhu C, Harper JW.A premature-termination mutation in the Mus musculus cyclin-dependent kinase 3 gene.Proc Natl Acad Sci U S A 2001 Feb 13;98(4):1682-6.
  11172011
• Goldberg AL, Elledge SJ, Harper JW.The cellular chamber of doom.Sci Am 2001 Jan;284(1):68-73.
  11132426
• Schulman BA, Carrano AC, Jeffrey PD, Bowen Z, Kinnucan ER, Finnin MS, Elledge SJ, Harper JW, Pagano M, Pavletich NP.Insights into SCF ubiquitin ligases from the structure of the Skp1-Skp2 complex.Nature 2000 Nov 16;408(6810):381-6.
  11099048
• Ma T, Van Tine BA, Wei Y, Garrett MD, Nelson D, Adams PD, Wang J, Qin J, Chow LT, Harper JW.Cell cycle-regulated phosphorylation of p220(NPAT) by cyclin E/Cdk2 in Cajal bodies promotes histone gene transcription.Genes Dev 2000 Sep 15;14(18):2298-313.
  10995387
• Stepanova L, Finegold M, DeMayo F, Schmidt EV, Harper JW.The oncoprotein kinase chaperone CDC37 functions as an oncogene in mice and collaborates with both c-myc and cyclin D1 in transformation of multiple tissues.Mol Cell Biol 2000 Jun;20(12):4462-73.
  10825210
• Stepanova L, Yang G, DeMayo F, Wheeler TM, Finegold M, Thompson TC, Harper JW.Induction of human Cdc37 in prostate cancer correlates with the ability of targeted Cdc37 expression to promote prostatic hyperplasia.Oncogene 2000 Apr 27;19(18):2186-93.
  10822368
• Lin BY, Ma T, Liu JS, Kuo SR, Jin G, Broker TR, Harper JW, Chow LT.HeLa cells are phenotypically limiting in cyclin E/CDK2 for efficient human papillomavirus DNA replication.J Biol Chem 2000 Mar 3;275(9):6167-74.
  10692408
• Shapiro GI, Harper JW.Anticancer drug targets: cell cycle and checkpoint control.J Clin Invest 1999 Dec;104(12):1645-53.
  10606615
• Harper JW, Elledge SJ.Skipping into the E2F1-destruction pathway.Nat Cell Biol 1999 May;1(1):E5-7.
  10559870
• Winston JT, Chu C, Harper JW.Culprits in the degradation of cyclin E apprehended.Genes Dev 1999 Nov 1;13(21):2751-7.
  10557204
• Wang Y, Penfold S, Tang X, Hattori N, Riley P, Harper JW, Cross JC, Tyers M.Deletion of the Cul1 gene in mice causes arrest in early embryogenesis and accumulation of cyclin E.Curr Biol 1999 Oct 21;9(20):1191-4.
  10531039
• Winston JT, Koepp DM, Zhu C, Elledge SJ, Harper JW.A family of mammalian F-box proteins.Curr Biol 1999 Oct 21;9(20):1180-2.
  10531037
• Erdamar S, Yang G, Harper JW, Lu X, Kattan MW, Thompson TC, Wheeler TM.Levels of expression of p27KIP1 protein in human prostate and prostate cancer: an immunohistochemical analysis.Mod Pathol 1999 Aug;12(8):751-5.
  10463475
• Kitagawa K, Skowyra D, Elledge SJ, Harper JW, Hieter P.SGT1 encodes an essential component of the yeast kinetochore assembly pathway and a novel subunit of the SCF ubiquitin ligase complex.Mol Cell 1999 Jul;4(1):21-33.
  10445024
• Koepp DM, Harper JW, Elledge SJ.How the cyclin became a cyclin: regulated proteolysis in the cell cycle.Cell 1999 May 14;97(4):431-4.
  10338207
• Skowyra D, Koepp DM, Kamura T, Conrad MN, Conaway RC, Conaway JW, Elledge SJ, Harper JW.Reconstitution of G1 cyclin ubiquitination with complexes containing SCFGrr1 and Rbx1.Science 1999 Apr 23;284(5414):662-5.
  10213692
• Kamura T, Koepp DM, Conrad MN, Skowyra D, Moreland RJ, Iliopoulos O, Lane WS, Kaelin WG, Elledge SJ, Conaway RC, Harper JW, Conaway JW.Rbx1, a component of the VHL tumor suppressor complex and SCF ubiquitin ligase.Science 1999 Apr 23;284(5414):657-61.
  10213691
• Winston JT, Strack P, Beer-Romero P, Chu CY, Elledge SJ, Harper JW.The SCFbeta-TRCP-ubiquitin ligase complex associates specifically with phosphorylated destruction motifs in IkappaBalpha and beta-catenin and stimulates IkappaBalpha ubiquitination in vitr
  9990852
• Zhang P, Wong C, Liu D, Finegold M, Harper JW, Elledge SJ.p21(CIP1) and p57(KIP2) control muscle differentiation at the myogenin step.Genes Dev 1999 Jan 15;13(2):213-24.
  9925645
• Ma T, Zou N, Lin BY, Chow LT, Harper JW.Interaction between cyclin-dependent kinases and human papillomavirus replication-initiation protein E1 is required for efficient viral replication.Proc Natl Acad Sci U S A 1999 Jan 19;96(2):382-7.
  9892642
• Adams PD, Li X, Sellers WR, Baker KB, Leng X, Harper JW, Taya Y, Kaelin WG.Retinoblastoma protein contains a C-terminal motif that targets it for phosphorylation by cyclin-cdk complexes.Mol Cell Biol 1999 Feb;19(2):1068-80.
  9891042
• Zhang P, Wong C, DePinho RA, Harper JW, Elledge SJ.Cooperation between the Cdk inhibitors p27(KIP1) and p57(KIP2) in the control of tissue growth and development.Genes Dev 1998 Oct 15;12(20):3162-7.
  9784491
• Callahan MA, Handley MA, Lee YH, Talbot KJ, Harper JW, Panganiban AT.Functional interaction of human immunodeficiency virus type 1 Vpu and Gag with a novel member of the tetratricopeptide repeat protein family.J Virol 1998 Oct;72(10):8461.
  9766974