WW Domain-Containing Oxidoreductase is a Potential Receptor for Sex Steroid Hormones

Su, Won-Pei; Chen, Shuhui; Chen, Szu-Jung; Chou, Pei‐Yi; Huang, Chun-Cheng; Chang, Nan‐Shan

doi:10.5772/26043

Cited by 9 publications

(27 citation statements)

References 84 publications

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“…The full-length WWOX protein is composed of two N -terminal WW domains, a C -terminal short-chain alcohol dehydrogenase/reductase (SDR) domain, and a proapoptotic C -terminal tail D3 (Chang et al, 2001, 2007, 2010; Aqeilan et al, 2004, 2007; Hong et al, 2007; Salah et al, 2012) (Figure 1). WWOX may act as an alternative receptor for sex steroid hormones, since its SDR domain possesses an NSYK motif capable of interacting with androgen and estrogen (Chang et al, 2005a; Su et al, 2012). …”

Section: Ww Domain-containing Oxidoreductase Wwoxmentioning

confidence: 99%

“…WWOX contains two N -terminal WW domains, a C -terminal short-chain alcohol dehydrogenase/reductase (SDR) domain, and a D3 region. A nuclear localization signal (NLS) is in between the WW domains (Chang et al, 2003, 2007; Del Mare et al, 2011; Salah et al, 2012; Su et al, 2012; reviews). The SDR domain possesses a mitochondria-binding region.…”

Section: Ww Domain-containing Oxidoreductase Wwoxmentioning

confidence: 99%

“…The first WW domain of WWOX may interact with proteins possessing a PPxY motif(s) such as AP-2γ, p73, ErbB4, Ezrin, SIMPLE, c-Jun, RUNX4, and many others (Chang et al, 2007; Salah et al, 2012; Su et al, 2012; Figure 1). Transiently overexpressed WWOX binds transcription factors AP-2, p73, and c-Jun and block their nuclear relocation in vitro , which suppresses cancer cell survival (Salah et al, 2012).…”

Section: Ww Domain-containing Oxidoreductase Wwoxmentioning

confidence: 99%

“…Overexpressed WWOX induces apoptosis and inhibits proliferation of human hepatic carcinoma cells (Hu et al, 2012) and many cancer cell types (Chang et al, 2007, 2010; Salah et al, 2012; Su et al, 2012). WWOX enhances the cytotoxic function of tumor necrosis factor by down-regulating apoptosis inhibitor Bcl-2 and Bcl-xL and up-regulating apoptotic p53 (Chang et al, 2001).…”

Section: Ww Domain-containing Oxidoreductase Wwoxmentioning

confidence: 99%

“…In most cases, we have shown that p53 functionally interacts with WWOX, and both proteins induce apoptosis in a synergistic manner (Chang et al, 2001, 2003, 2005a,b, 2007, 2010, 2012; Su et al, 2012). A likely scenario is that p53-binding proteins, which are present in GBMs, may interfere with the apoptotic function of WWOX and p53.…”

Section: Perspectivesmentioning

confidence: 99%

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Tumor Suppressor WWOX and p53 Alterations and Drug Resistance in Glioblastomas

Chiang¹,

Chou²,

Wang³

et al. 2013

Front. Oncol.

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Tumor suppressor p53 are frequently mutated in glioblastomas (GBMs) and appears to contribute, in part, to resistance to temozolomide (TMZ) and therapeutic drugs. WW domain-containing oxidoreductase WWOX (FOR or WOX1) is a proapoptotic protein and is considered as a tumor suppressor. Loss of WWOX gene expression is frequently seen in malignant cancer cells due to promoter hypermethylation, genetic alterations, and translational blockade. Intriguingly, ectopic expression of wild type WWOX preferentially induces apoptosis in human glioblastoma cells harboring mutant p53. WWOX is known to physically bind and stabilize wild type p53. Here, we provide an overview for the updated knowledge in p53 and WWOX, and postulate potential scenarios that wild type and mutant p53, or isoforms, modulate the apoptotic function of WWOX. We propose that triggering WWOX activation by therapeutic drugs under p53 functional deficiency is needed to overcome TMZ resistance and induce GBM cell death.

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Section: Ww Domain-containing Oxidoreductase Wwoxmentioning

confidence: 99%

Section: Ww Domain-containing Oxidoreductase Wwoxmentioning

confidence: 99%

Section: Ww Domain-containing Oxidoreductase Wwoxmentioning

confidence: 99%

Section: Ww Domain-containing Oxidoreductase Wwoxmentioning

confidence: 99%

Section: Perspectivesmentioning

confidence: 99%

See 3 more Smart Citations

Tumor Suppressor WWOX and p53 Alterations and Drug Resistance in Glioblastomas

Chiang¹,

Chou²,

Wang³

et al. 2013

Front. Oncol.

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WWOX and metabolic regulation in normal and pathological conditions

Baryła

Kośla

2022

J Mol Med

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WW domain-containing oxidoreductase (WWOX) spans the common fragile site FRA16D. There is evidence that translocations and deletions affecting WWOX accompanied by loss of expression are frequent in many cancers and often correlate with a worse prognosis. Additionally, WWOX germline mutations were also found to be the cause of pathologies of brain development. Because WWOX binds to some transcription factors, it is a modulator of many cellular processes, including metabolic processes. Recently, studies have linked WWOX to familial dyslipidemias, osteopenia, metabolic syndrome, and gestational diabetes, confirming its role as a regulator of steroid, cholesterol, glucose, and normal bone metabolism. The WW domain of WWOX is directly engaged in the control of the activity of transcription factors such as HIF1α and RUNX2; therefore, WWOX gene alterations are associated with some metabolic abnormalities. Presently, most interest is devoted to the associations between WWOX and glucose and basic energy metabolism disturbances. In particular, its involvement in the initiation of the Warburg effect in cancer or gestational diabetes and type II diabetes is of interest. This review is aimed at systematically and comprehensively presenting the current state of knowledge about the participation of WWOX in the metabolism of healthy and diseased organisms.

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Phosphorylation/de-phosphorylation in specific sites of tumor suppressor WWOX and control of distinct biological events

Huang

Chang

2018

Exp Biol Med (Maywood)

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Abnormal differentiation and growth of hematopoietic stem cells cause the development of hematopoietic diseases and hematopoietic malignancies. However, the molecular events underlying leukemia development are not well understood. In our recent study, we have demonstrated that calcium ionophore and phorbol ester force the differentiation of T lymphoblastic leukemia. The event involves a newly identified IκBα/WWOX/ERK signaling, in which WWOX is Ser14 phosphorylated. Additional evidence also reveals that pS14-WWOX is involved in enhancing cancer progression and metastasis and facilitating neurodegeneration. In this mini-review, we update the current knowledge for the functional roles of WWOX under physiological and pathological settings, and provide new insights regarding pS14-WWOX in T leukemia cell maturation, and switching the anticancer pY33-WWOX to pS14-WWOX for cancer promotion and disease progression. Impact statement WWOX was originally designated as a tumor suppressor. However, human newborns deficient in WWOX do not spontaneously develop tumors. Activated WWOX with Tyr33 phosphorylation is present in normal tissues and organs. However, when pY33-WWOX is overly induced under stress conditions, it becomes apoptotic to eliminate damaged cells. Notably, WWOX with Ser14 phosphorylation is upregulated in the lesions of cancer, as well as in the brain hippocampus and cortex with Alzheimer's disease. Suppression of pS14-WWOX by Zfra reduces cancer growth and mitigates Alzheimer's disease progression, suggesting that pS14-WWOX facilitates disease progression. pS14-WWOX can be regarded as a marker of disease progression.

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WW Domain-Containing Oxidoreductase is a Potential Receptor for Sex Steroid Hormones

Cited by 9 publications

References 84 publications

Tumor Suppressor WWOX and p53 Alterations and Drug Resistance in Glioblastomas

Tumor Suppressor WWOX and p53 Alterations and Drug Resistance in Glioblastomas

WWOX and metabolic regulation in normal and pathological conditions

Phosphorylation/de-phosphorylation in specific sites of tumor suppressor WWOX and control of distinct biological events

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