DF/HCC Program Affiliation

Cancer Cell Biology
Cancer Genetics

Research Abstract

Our laboratory is addressing two questions relevent to tumorigenesis including how mitotic checkpoint proteins prevent chromosomal aneuploidy and the function of the p53 homologs, p73 and p63. The mitotic checkpoint ensures the proper alignment of chromosomes prior to chromosome segregation at anaphase. We have cloned the mammalian homologs of Bub1,Bub3, and a Mad3-like protein, genes in yeast required for cell cycle arrest in response to spindle damage. Experiments with Bub1, Bub3 and the Mad3-like protein in mammalian cells show that they target to the kinetochore of prophase cells and play a crucial role in monitoring chromosome alignment. As chromosome stability is compromised in many human tumors, we are using dominant-negative versions of Bub1 and the Mad3-like protein in mice to determine the consequences of weakend mitotic checkpoints on development and tumorigenesis.

p73 and p63 are recently discovered homologs of p53. We have produced mouse strains lacking p73 and p63 to address their function. Unlike the p53 null mice, those lacking p73 display multiple defects affecting the immune and nervous systems. The p63 mouse displays a separate set of defects involving proliferation and stem cell identity. We are using cell and molecular biology to determine the roles of the various p53 family members in cell cycle control, development, and in tumor formation.

Publications

• Yang A, Zhu Z, Kapranov P, McKeon F, Church GM, Gingeras TR, Struhl K.Relationships between p63 binding, DNA sequence, transcription activity, and biological function in human cells.Mol Cell 2006 Nov 17;24(4):593-602.
  17188034
• Urist MJ, Di Como CJ, Lu ML, Charytonowicz E, Verbel D, Crum CP, Ince TA, McKeon FD, Cordon-Cardo C.Loss of p63 expression is associated with tumor progression in bladder cancer.Am J Pathol 2002 Oct;161(4):1199-206.
  12368193
• Wang TY, Chen BF, Yang YC, Chen H, Wang Y, Cviko A, Quade BJ, Sun D, Yang A, McKeon FD, Crum CP.Histologic and immunophenotypic classification of cervical carcinomas by expression of the p53 homologue p63: a study of 250 cases.Hum Pathol 2001 May;32(5):47
  11381365
• Yang A, Schweitzer R, Sun D, Kaghad M, Walker N, Bronson RT, Tabin C, Sharpe A, Caput D, Crum C, McKeon F.p63 is essential for regenerative proliferation in limb, craniofacial and epithelial development.Nature 1999 Apr 22;398(6729):714-8.
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• Yang A, Kaghad M, Wang Y, Gillett E, Fleming MD, Dötsch V, Andrews NC, Caput D, McKeon F.p63, a p53 homolog at 3q27-29, encodes multiple products with transactivating, death-inducing, and dominant-negative activities.Mol Cell 1998 Sep;2(3):305-16.
  9774969
• Taylor SS, McKeon F.Kinetochore localization of murine Bub1 is required for normal mitotic timing and checkpoint response to spindle damage.Cell 1997 May 30;89(5):727-35.
  9182760
• Ryeom S, Baek KH, Rioth MJ, Lynch RC, Zaslavsky A, Birsner A, Yoon SS, McKeon F.Targeted deletion of the calcineurin inhibitor DSCR1 suppresses tumor growth.Cancer Cell 2008 May;13(5):420-31.
  18455125
• Ha GH, Baek KH, Kim HS, Jeong SJ, Kim CM, McKeon F, Lee CW.p53 activation in response to mitotic spindle damage requires signaling via BubR1-mediated phosphorylation.Cancer Res 2007 Aug 1;67(15):7155-64.
  17671183
• Davies KJ, Ermak G, Rothermel BA, Pritchard M, Heitman J, Ahnn J, Henrique-Silva F, Crawford D, Canaider S, Strippoli P, Carinci P, Min KT, Fox DS, Cunningham KW, Bassel-Duby R, Olson EN, Zhang Z, Williams RS, Gerber HP, Perez-Riba M, Seo H, Cao X, Klee C
  17595344
• Lee Y, Kim KR, McKeon F, Yang A, Boyd TK, Crum CP, Parast MM.A unifying concept of trophoblastic differentiation and malignancy defined by biomarker expression.Hum Pathol 2007 Mar 29.
  17397906
• Suh EK, Yang A, Kettenbach A, Bamberger C, Michaelis AH, Zhu Z, Elvin JA, Bronson RT, Crum CP, McKeon F.p63 protects the female germ line during meiotic arrest.Nature 2006 Nov 30;444(7119):624-8.
  17122775
• Lee Y, Miron A, Drapkin R, Nucci MR, Medeiros F, Saleemuddin A, Garber J, Birch C, Mou H, Gordon RW, Cramer DW, McKeon FD, Crum CP.A candidate precursor to serous carcinoma that originates in the distal fallopian tube.J Pathol 2007 Jan;211(1):26-35.
  17117391
• Signoretti S, Pires MM, Lindauer M, Horner JW, Grisanzio C, Dhar S, Majumder P, McKeon F, Kantoff PW, Sellers WR, Loda M.p63 regulates commitment to the prostate cell lineage.Proc Natl Acad Sci U S A 2005 Aug 9;102(32):11355-60.
  16051706
• Witkiewicz AK, Hecht JL, Cviko A, McKeon FD, Ince TA, Crum CP.Microglandular hyperplasia: a model for the de novo emergence and evolution of endocervical reserve cells.Hum Pathol 2005 Feb;36(2):154-61.
  15754292
• Venkatesh N, Feng Y, DeDecker B, Yacono P, Golan D, Mitchison T, McKeon F.Chemical genetics to identify NFAT inhibitors: potential of targeting calcium mobilization in immunosuppression.Proc Natl Acad Sci U S A 2004 Jun 15;101(24):8969-74.
  15184684
• Ellisen LW, Ramsayer KD, Johannessen CM, Yang A, Beppu H, Minda K, Oliner JD, McKeon F, Haber DA.REDD1, a developmentally regulated transcriptional target of p63 and p53, links p63 to regulation of reactive oxygen species.Mol Cell 2002 Nov;10(5):995-1005.
  12453409
• Ince TA, Cviko AP, Quade BJ, Yang A, McKeon FD, Mutter GL, Crum CP.p63 Coordinates anogenital modeling and epithelial cell differentiation in the developing female urogenital tract.Am J Pathol 2002 Oct;161(4):1111-7.
  12368184
• Quade BJ, Yang A, Wang Y, Sun D, Park J, Sheets EE, Cviko A, Federschneider JM, Peters R, McKeon FD, Crum CP.Expression of the p53 homologue p63 in early cervical neoplasia.Gynecol Oncol 2001 Jan;80(1):24-9.
  11136565
• O'Connell JT, Mutter GL, Cviko A, Nucci M, Quade BJ, Kozakewich HP, Neffen E, Sun D, Yang A, McKeon FD, Crum CP.Identification of a basal/reserve cell immunophenotype in benign and neoplastic endometrium: a study with the p53 homologue p63.Gynecol Oncol 2
  11136566
• Signoretti S, Waltregny D, Dilks J, Isaac B, Lin D, Garraway L, Yang A, Montironi R, McKeon F, Loda M.p63 is a prostate basal cell marker and is required for prostate development.Am J Pathol 2000 Dec;157(6):1769-75.
  11106548
• Park JJ, Sun D, Quade BJ, Flynn C, Sheets EE, Yang A, McKeon F, Crum CP.Stratified mucin-producing intraepithelial lesions of the cervix: adenosquamous or columnar cell neoplasia?.Am J Surg Pathol 2000 Oct;24(10):1414-9.
  11023104
• Cviko A, Briem B, Granter SR, Pinto AP, Wang TY, Yang YC, Chen BF, Yang A, Sheets EE, McKeon FD, Crum CP.Adenoid basal carcinomas of the cervix: a unique morphological evolution with cell cycle correlates.Hum Pathol 2000 Jun;31(6):740-4.
  10872669
• Yang A, Walker N, Bronson R, Kaghad M, Oosterwegel M, Bonnin J, Vagner C, Bonnet H, Dikkes P, Sharpe A, McKeon F, Caput D.p73-deficient mice have neurological, pheromonal and inflammatory defects but lack spontaneous tumours.Nature 2000 Mar 2;404(6773):99
  10716451
• Wolf DA, McKeon F, Jackson PK.Budding yeast Cdc6p induces re-replication in fission yeast by inhibition of SCF(Pop)-mediated proteolysis.Mol Gen Genet 1999 Oct;262(3):473-80.
  10589835
• Celli J, Duijf P, Hamel BC, Bamshad M, Kramer B, Smits AP, Newbury-Ecob R, Hennekam RC, Van Buggenhout G, van Haeringen A, Woods CG, van Essen AJ, de Waal R, Vriend G, Haber DA, Yang A, McKeon F, Brunner HG, van Bokhoven H.Heterozygous germline mutations
  10535733
• Tivol EA, Boyd SD, McKeon S, Borriello F, Nickerson P, Strom TB, Sharpe AH.CTLA4Ig prevents lymphoproliferation and fatal multiorgan tissue destruction in CTLA-4-deficient mice.J Immunol 1997 Jun 1;158(11):5091-4.
  9164923
• Milan D, Griffith J, Su M, Price ER, McKeon F.The latch region of calcineurin B is involved in both immunosuppressant-immunophilin complex docking and phosphatase activation.Cell 1994 Nov 4;79(3):437-47.
  7525078
• Walsh CT, Zydowsky LD, McKeon FD.Cyclosporin A, the cyclophilin class of peptidylprolyl isomerases, and blockade of T cell signal transduction.J Biol Chem 1992 Jul 5;267(19):13115-8.
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