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.
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• 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.
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• 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
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• 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.
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• 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.
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