The Role of the Chkl Kinase in Cell Cycle Checkpoint Response in Breast Epithelial Cells

P63 IS A RECENTLY IDENTIFIED HOMOLOG OF P53 THAT IS FOUND IN THE BASAL LAYER OF SEVERAL EPITHELIAL TISSUES SUCH AS THE EPIDERMIS, ORAL MUCOSA, PROSTATE, UROGENITAL TRACT, AND MAMMARY GLAND. Studies with p63-/-mice and analysis of several human autosomal dominant disorders with germline p63 mutations...

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Bibliographic Details
Main Authors: Westfall, Matthew D, Pietenpol, Jennifer A
Format: Report
Language:English
Subjects:
Anatomy and Physiology
Biochemistry
BREAST CANCER
BREAST EPITHELIAL CELLS
CELL CYCLES
CELLS(BIOLOGY)
CHK1 KINASE
CULTURES(BIOLOGY)
EPIDERMIS
EPITHELIUM
GENETIC ENGINEERING
HMEC(HUMAN MAMMARY EPITHELIAL CELLS)
IN VIVO ANALYSIS
MAMMARY GLANDS
Medicine and Medical Research
MUCOUS MEMBRANES
MUTATIONS
OPTIMIZATION
ORAL INTAKE
P63
PHOSPHORYLATION
PROTEINS
STEM CELLS
TISSUES(BIOLOGY)
URINARY SYSTEM
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Summary:P63 IS A RECENTLY IDENTIFIED HOMOLOG OF P53 THAT IS FOUND IN THE BASAL LAYER OF SEVERAL EPITHELIAL TISSUES SUCH AS THE EPIDERMIS, ORAL MUCOSA, PROSTATE, UROGENITAL TRACT, AND MAMMARY GLAND. Studies with p63-/-mice and analysis of several human autosomal dominant disorders with germline p63 mutations suggest p63 involvement in maintaining epithelial stem cell populations. However, the biochemical mechanisms by which p63 functions are not well understood. The goals of the current study were to determine the splice variants that are expressed in primary human mammary epithelial cells (HMECs) and the biochemical activity p63 has in these epithelial cell populations. Progress to date includes (i) Cloning of p63 splice variants and development of assay systems in primary epidermal cell cultures to analyze p63 expression and biochemical activity; (ii) determining that p63 represses transcription and binds directly to p53 consensus sites in the p2l and l4-3-3o promoters in ritro and in vivo in HEKs and HMECs; (iii) development of optimal growth conditions for primary human mammary epithelial cells; (iv) determining that %Np63Q is the predominant splice variant expressed in HMECs; (v) determining that %Np63a is a phosphoprotein and how phosphorylation affects p63 function. It is critical to obtain a more thorough understanding of how p63 works at the rnolecular level in HMECs to better understand the role of p63 in breast cancer development. The original document contains color images. All DTIC reproductions will be in black and white.