Nuclear translocation controlled by alternatively spliced isoforms inactivates the QUAKING apoptotic inducer.
The quaking viable mice have myelination defects and develop a characteristic tremor 10 d after birth. The quaking gene encodes at least five alternatively spliced QUAKING (QKI) isoforms that differ in their C-terminal 8--30-amino-acid sequence. The reason for the existence of the different QKI isoforms and their function are unknown. Here we show that only one QKI isoform, QKI-7, can induce apoptosis in fibroblasts and primary rat oligodendrocytes. Heterodimerization of the QKI isoforms results in the nuclear translocation of QKI-7 and the suppression of apoptosis. The unique C-terminal 14 amino acids of QKI-7 confers the ability to induce apoptosis to heterologous proteins such as the green fluorescent protein and a QKI-related protein, Caenorhabditis elegans GLD-1. Thus, the unique C-terminal sequences of QKI-7 may function as a life-or-death 'sensor' that monitors the balance between the alternatively spliced QKI isoforms. Moreover, our findings suggest that nuclear translocation is a novel mechanism of inactivating apoptotic inducers.
Pilotte
J
J
Terry 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.
Larocque
D
D
Richard
S
S
D016475:3T3 Cells / Q000166:cytology; D000256:Adenoviridae / Q000235:genetics; D017398:Alternative Splicing; D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D002467:Cell Nucleus / Q000378:metabolism*; D002478:Cells, Cultured; D003711:Demyelinating Diseases; D019281:Dimerization; D005822:Genetic Vectors / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008821:Mice, Quaking; D008969:Molecular Sequence Data; D009836:Oligodendroglia / Q000166:cytology; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D055503:Protein Multimerization; D021382:Protein Sorting Signals / Q000502:physiology; D021381:Protein Transport; D016601:RNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000502:physiology; D016415:Sequence Alignment; D013329:Structure-Activity Relationship; D013752:Tetracycline / Q000494:pharmacology; D015533:Transcriptional Activation / Q000187:drug effects; D014162:Transfection
D020033:Protein Isoforms; D021382:Protein Sorting Signals; C490832:QKI protein, human; C098217:Qk protein, mouse; D016601:RNA-Binding Proteins; D011993:Recombinant Fusion Proteins; D013752:Tetracycline