Abstract
The human and mouse WWOX/Wwox gene encodes a candidate tumor suppressor WW domain-containing oxidoreductase protein. This gene is located on a common fragile site FRA16D. WWOX participates in a variety of cellular events and acts as a transducer in the many signal pathways, including TNF, chemotherapeutic drugs, UV irradiation, Wnt, TGF-β, C1q, Hyal-2, sex steroid hormones, and others. While transiently overexpressed WWOX restricts relocation of transcription factors to the nucleus for suppressing cancer survival, physiological relevance of this regard in vivo has not been confirmed. Unlike many tumor suppressor genes, mutation of WWOX is rare, raising a question whether WWOX is a driver for cancer initiation. WWOX/Wwox was initially shown to play a crucial role in neural development and in the pathogenesis of Alzheimer's disease and neuronal injury. Later on, WWOX/Wwox was shown to participate in the development of epilepsy, mental retardation, and brain developmental defects in mice, rats and humans. Up to date, most of the research and review articles have focused on the involvement of WWOX in cancer. Here, we review the role of WWOX in neural injury and neurological diseases, and provide perspectives for the WWOX-regulated neurodegeneration.
Highlights
Human and mouse WWOX/Wwox gene was first cloned in year 2000 [1-5; reviews]
We have shown that WWOX is an inhibitor of neurodegeneration, because of its interaction with tau and inhibition of enzyme-dependent Tau hyperphosphorylation [16,17]
Substantial evidence has shown that WWOX participates in the control of the function of transcription factors in vivo
Summary
Human and mouse WWOX/Wwox gene was first cloned in year 2000 [1-5; reviews]. Later on, the mouse Wwox genome, which has one million bases, was isolated [6]. Hyal-2 is internalized and recruits WWOX via binding to the SDR domain, and the resulting WWOX/ Hyal-2 complex binds Smad4 and is accumulated in the nucleus, which affects cell survival or death [15]. WWOX is involved in binding and regulating GSK3β activity, and this limits Tau hyperphosphorylation, neurite outgrowth in neuronal differentiation, and formation of neurofibrillary tangles (NFTs) and senile plaques in Alzheimer’s disease (AD) [16,17,22].
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