Investigation of the Function and Regulatory Mechanisms of the Mammalian Target of Rapamycin

Bachmann, Rebecca Anne

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Description

Title

Investigation of the Function and Regulatory Mechanisms of the Mammalian Target of Rapamycin

Author(s)

Bachmann, Rebecca Anne

Issue Date

2003

Doctoral Committee Chair(s)

Chen, Jie

Department of Study

Biochemistry

Discipline

Biochemistry

Degree Granting Institution

University of Illinois at Urbana-Champaign

Degree Name

Ph.D.

Degree Level

Dissertation

Keyword(s)

Health Sciences, Pharmacology

Language

eng

Abstract

Unexpectedly, mTOR has been found to shuttle between the nucleus and the cytoplasm, and this shuttling is required for its cytoplasmic signaling. I have further investigated the regulation and function of mTOR cytoplasmic-nuclear shuttling. A systematic screen of mTOR revealed a rev-like NES sequence within mTOR at amino acids 1281--1289, which displayed robust nuclear export activity in a reporter system. Mutation of the conserved leucines within this export site resulted in a loss of downstream signaling in vivo, despite retention of mTOR catalytic activity. Interestingly, the mTOR 1281--1289L/A mutant showed cytoplasmic staining similar to wild type mTOR, and did not accumulate in the nucleus upon LMB treatment. This suggests that the 1281--1289L/A mutations in mTOR disrupt nucleocytoplasmic shuttling activity. The nucleocytoplasmic shuttling of mTOR is likely a mechanism to lessen the probability of aberrant signaling, a necessary control for a protein that has an essential role in cell growth and proliferation.

Graduation Semester

2003

Type of Resource

text

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