Investigation of the p53-dependent apoptosis versus arrest decision through analysis of Prep gene regulation

The p53 tumor suppressor gene is thought to play a critical role in the maintenance of genetic integrity by virtue of its ability to check the growth of abnormal or damaged cells through initiation of the cell cycle arrest and apoptosis pathways. p53 itself is mutated in roughly half of all human tumors and is likely to be inactivated through mutations in other components of the stress response pathway in the remaining cases, highlighting the centrality of p53 function to effective tumor suppression. The vast majority of p53 mutations disrupt its sequence-specific DNA binding function, compromising its ability to activate a large array of target genes involved in apoptosis, arrest, DNA repair, senescence, differentiation and other cellular functions. While the catalog of target genes is rapidly expanding, our understanding of the effector pathways downstream of p53 and the regulatory networks that govern their expression remains incomplete. Subtle changes in cellular environment and cell type specific factors can drastically affect the decision to pause and repair accumulated damage, or to commit cellular suicide to prevent the propagation of damaged genetic material. Our understanding of this life or death decision is still rudimentary. The work presented here represents an attempt to uncover mechanisms underlying the decision to initiate apoptosis or cell cycle arrest in a simple model system. Mouse embryo fibroblasts normally respond to DNA damage by undergoing cell cycle arrest, but can be sensitized to initiate p53-dependent apoptosis by the oncoprotein E1A. Through a subtractive hybridization screen, the Perp gene was identified as a transcript strongly upregulated in cells initiating p53-dependent apoptosis compared to those undergoing cell cycle arrest.

Department dc:contributor.department

Massachusetts Institute of Technology. Dept. of Biology.

Grantor dc:publisher

Massachusetts Institute of Technology

Year dc:date.issued

2003

Author dc:creator

• Reczek, Elizabeth E. (Elizabeth Emily), 1975-

Advisor dc:contributor.advisor

• Tyler Jacks.

• Biology.

Statement dc:rights

• M.I.T. theses are protected by copyright. They may be viewed from this source for any purpose, but reproduction or distribution in any format is prohibited without written permission. See provided URL for inquiries about permission.

Licence dc:rights.uri

• http://dspace.mit.edu/handle/1721.1/7582

Language dc:language.iso

eng

Handle dc:identifier.uri

http://hdl.handle.net/1721.1/29595

OAI identifier oai:identifier

oai:dspace.mit.edu:1721.1/29595