Death by Frustration: How Defects in Cell Differentiation Trigger Apoptosis

Author

Ann H. Tang

Date of Award

2007

Document Type

Thesis

Degree Name

Doctor of Philosophy (PhD)

RU Laboratory

Steller Laboratory

Abstract

Apoptosis plays a crucial role in the growth, development, and homeostasis of multicellular organisms by removing excess cells and sculpting tissues. The implications of its misregulation in diseases such as cancer, neurodegeneration, and autoimmunity bespeak of its importance. A family of proteases called caspases brings about the orderly deconstruction of a cell through an evolutionarily-conserved process. A bewildering number of molecules have been implicated to either directly or indirectly regulate these enzymes. Since the net outcome between inhibitory and activational mechanisms ultimately determines a cell’s fate, caspases and their regulation still continue to be subjects of intense study. Studies with dcp-1 described here have clarified its role as a Drosophila effector caspase. From the original descriptions of its somatic phenotypes, a possible role for dcp-1 in cell proliferation was initially explored, but these phenotypes were eventually found to be associated with a disruption in another gene encoded in the same locus. RNAi studies with dcp-1 and drice, another effector caspase, have provided in vivo confirmation of their epistatic relationship to rpr, hid, and grim and have revealed that they may work synergistically. rpr indirectly activates caspases by derepressing their inhibitors, and many proapoptotic signals trigger its transcriptional upregulation. An analysis of its promoter described here has furthered the understanding of how developmental mutations cue rpr transcription. As a consequence of signaling resulting from developmentally aberrant cells, rpr is transcriptionally activated via different elements in its promoter region, rather than through a single one, suggesting the role of different pathways and hence different transcription factors. A yeast 1-hybrid assay performed with a narrow region that can mediate upregulation in crb and srp3 backgrounds has led to the identification of a transcriptional modulator of rpr, p8. Its mammalian homolog has been implicated in stress response and apoptosis. The induced RNA and protein levels of p8, the RNA in situ pattern, and a reduction of reporter signal in p8 mutants in crb and srp3 backgrounds support a role for p8 in transducing a pro-apoptotic response resulting from developmental mutants to the activation of rpr transcription.

Comments

A Thesis Presented to the Faculty of The Rockefeller University In Partial Fulfillment of the Requirements for The degree of Doctor of Philosophy

Recommended Citation

Tang, Ann H., "Death by Frustration: How Defects in Cell Differentiation Trigger Apoptosis" (2007). Student Theses and Dissertations. 187.
https://digitalcommons.rockefeller.edu/student_theses_and_dissertations/187