Nuclear translocation controlled by alternatively spliced isoforms inactivates the QUAKING apoptotic inducer

Abstract

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. Apoptosis, or programmed cell death, is a physiological process characterized by a cascade of events culminating in the destruction of the cell. There are numerous protein families that have been shown to induce apoptosis including the TNF

Expression of Hqk Encoding a KH RNA Binding Protein Is Altered in Human Glioma

“…13,17) These results clearly suggest the involvement of the gld-1 in the regulation of cell proliferation. More importantly, Pilotte et al 33) recently reported that the QKI-7 isoform could act as a potent apoptosis inducer in vitro. QKI protein and possibly Hqk gene product function as RNA-binding proteins.…”

“…32) Furthermore, it was recently reported that one particular protein isoform of the qkI, QKI-7 is a potent inducer of apoptosis. 33) It is thus possible that the Hqk gene is involved in cell proliferation as well as disease development processes. As an initial step towards understanding the potential roles of Hqk gene in disease development, we have isolated both cDNA and genomic clones for Hqk, characterized its genomic structure and determined its expression pattern, as well as the chromosomal location of Hqk.…”

Impaired cytoskeletal organization and membrane integrity in lens fibers of a Rho GTPase functional knockout transgenic mouse

“…Genes encoding several proapoptotic proteins, including JNK1, lymphotoxin beta-receptor, quaking protein-7 and granzyme F, [38][39][40] were strongly upregulated in C3 lenses. C3 toxin has been reported to activate the JNK stress-signaling pathway and increased apoptosis in cell culture systems.…”

kep1 interacts genetically with dredd / Caspase-8 , and kep1 mutants alter the balance of dredd isoforms

“…1). KH domain-containing RNA binding proteins have been proposed as a family of apoptotic inducers (2). For example, the mouse quaking (QKI) protein and the Drosophila Kep1 and Sam50 proteins are potent inducers of cell death in the absence of any other signal (2)(3)(4).…”

“…For example, the mouse quaking (QKI) protein and the Drosophila Kep1 and Sam50 proteins are potent inducers of cell death in the absence of any other signal (2)(3)(4). Expression of QKI causes apoptosis in transfected cells (4), and the C-terminal 14 aa of the QKI-7 isoform are necessary and sufficient to induce apoptosis (2). Kep1 (also referred to as Qkr58E-3; ref.…”