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Nuclear translocation controlled by alternatively spliced isoforms inactivates the QUAKING apoptotic inducer
J Pilotte1, D Larocque, S Richard
1Terry Fox Molecular Oncology Group and the Bloomfield Center for Research on Aging, Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, Montréal, Québec, H3T 1E2, Canada.
Genes & Development
|April 12, 2001
Summary
The quaking (QKI) gene produces multiple protein isoforms. Researchers found that only the QKI-7 isoform induces apoptosis, a process of cell death, which is suppressed upon heterodimerization.
Area of Science:
- Molecular Biology
- Neuroscience
- Cell Biology
Background:
- Quaking viable mice exhibit myelination defects and tremors due to mutations in the quaking gene.
- The quaking gene encodes at least five alternatively spliced QUAKING (QKI) isoforms with unknown functions.
- The specific roles of different QKI isoforms in cellular processes remain largely uncharacterized.
Purpose of the Study:
- To investigate the distinct functions of QKI isoforms.
- To elucidate the mechanism by which QKI isoforms regulate apoptosis.
- To understand the role of QKI isoform heterogeneity in cellular regulation.
Main Methods:
- Apoptosis assays in fibroblasts and primary rat oligodendrocytes.
- Expression and analysis of different QKI isoforms.
- Heterodimerization studies of QKI isoforms.
- Functional analysis of QKI isoform C-terminal domains using heterologous proteins.
Main Results:
- Only the QKI-7 isoform was found to induce apoptosis in tested cell types.
- Heterodimerization of QKI isoforms led to nuclear translocation of QKI-7 and suppressed apoptosis.
- The unique C-terminal 14 amino acids of QKI-7 are sufficient to confer apoptosis-inducing activity to other proteins.
- This suggests QKI-7's C-terminus acts as a sensor for isoform balance.
Conclusions:
- QKI-7 is a specific inducer of apoptosis among QKI isoforms.
- Nuclear translocation of QKI-7 is a novel mechanism for inactivating apoptosis.
- The C-terminal sequence of QKI-7 plays a critical role in regulating cell death and sensing isoform balance.