Characterization and use of the interaction between ATR suppression and P53 deficiency / David W. Schoppy.

Format:

Book

Manuscript

Thesis/Dissertation

Author/Creator:

Schoppy, David W.

Contributor:

Brown, Eric J., advisor.

George, Donna L., advisor.

University of Pennsylvania.

Language:

English

Subjects (All):

Penn dissertations--Cell and molecular biology.

Cell and molecular biology--Penn dissertations.

Cell and Molecular Biology.

Academic Dissertations as Topic.

Medical Subjects:

Cell and Molecular Biology.

Academic Dissertations as Topic.

Local Subjects:

Penn dissertations--Cell and molecular biology.

Cell and molecular biology--Penn dissertations.

Physical Description:

v, 138 pages : illustrations (some color) ; 29 cm

Production:

2011.

Summary:

p53 influences a staggering array of cellular processes that ultimately impact diverse aspects of normal physiology. Importantly, the majority of human cancers are functionally deficient in p53, and loss of this critical tumor suppressor is often associated with resistance to conventional chemotherapy. Efforts to identify novel therapeutic approaches to p53-deficienct malignancies have suggested that the ATR-CHK1 pathway may be a useful target, as suppression of ATR or CHK1 is especially toxic to model organisms lacking p53. Unfortunately, the precise nature of this interaction has remained poorly understood and its potential for use in a therapeutic setting is currently unclear. This thesis presents a detailed characterization of a synthetic lethal interaction between complete ATR loss and p53 deficiency in non-malignant tissues and provides evidence that this deleterious outcome is partly the product of a non-cell autonomous interaction. These findings are then applied to the clinically relevant problem of p53-deficient malignancies in the development and use of a novel genetic system to conditionally suppress, rather than eliminate, ATR in adult tissues and model p53-deficient cancers.

Notes:

Advisers: Eric J. Brown; Donna L. George.

Thesis (Ph.D. in Cell and Molecular Biology) -- University of Pennsylvania, 2011.

Includes bibliographical references.