Disease relevance of Wwox

• Tumorigenicity and in vitro growth of U2020 (Wwox-positive) lung cancer cells was unaffected by Wwox overexpression [1].
• PURPOSE: The WWOX gene is down-regulated in breast cancer and loss of Wwox expression correlates with important clinical features of breast cancer [2].
• By immunohistochemistry, we determined that progression of prostate from normal to hyperplasia, cancerous and metastatic stages positively correlate with upregulation and activation of WOX1 and WOX2 (FOR1/WWOXv2) [3].
• In contrast, breast cancer development to a premetastatic state is associated with upregulation and Tyr33 phosphorylation of cytosolic WOX1 and WOX2, followed by significant downregulation or absent expression during metastasis [3].

Psychiatry related information on Wwox

• Down-regulation of WW domain-containing oxidoreductase induces Tau phosphorylation in vitro. A potential role in Alzheimer's disease [4].

High impact information on Wwox

• It has been reported that phosphorylation of Wwox at Tyr33 stimulated its proapoptotic activity [5].
• Tyrosine phosphorylation of Wwox was critical for its degradation, as splice variant WwoxDelta5-8 that was not phosphorylated by Ack1 failed to undergo polyubiquitination and degradation [5].
• Primary androgen-independent prostate tumors but not benign prostate showed increased tyrosine-phosphorylated Ack1 and decreased Wwox [5].
• The activated WOX1 binds tumor suppressor p53, and both proteins may induce apoptosis synergistically [6].
• Knockdown of WOX1 protein expression by small interfering RNA resulted in L929 fibroblast resistance to apoptosis by tumor necrosis factor, staurosporine, UV light, and ectopic p53, indicating an essential role of WOX1 in stress stimuli-induced apoptosis [6].

Chemical compound and disease context of Wwox

• H1299 lung cancer cells, lacking Fhit, Wwox, p16(INK4a) and Rassf1a expression due to epigenetic modifications, were used to assess efficacy of epigenetically targeted protocols in suppressing growth of lung tumors, by injection of 5-aza-2-deoxycytidine (AZA) and trichostatin A (TSA) in nude mice with established H1299 tumors [7].

Biological context of Wwox

• Intratumoral Wwox restoration, through Ad-WWOX infection or endogenous Wwox reactivation by 5-aza-2'-deoxycytidine injection, suppressed tumor growth in nude mice by inducing apoptosis [2].
• Inhibition of Breast Cancer Cell Growth In vitro and In vivo: Effect of Restoration of Wwox Expression [2].
• Thus, WOX1 is a mitochondrial apoptogenic protein and an essential partner of p53 in cell death [8].
• In rd mice with an inherited retinal deficiency, upregulation of WOX1 and p-WOX1 in degenerated retina was observed with age [9].
• Hyaluronidases such as PH-20, Hyal-1 and Hyal-2 induce the expression of WOX1, and hyaluronidases and hyaluronan are involved in the embryonic development [10].

Anatomical context of Wwox

• WOX1 is mainly located in the mitochondria, and the mitochondrial targeting sequence was mapped within the ADH domain [8].
• Immunohistochemical analysis revealed that WOX1 was differentially expressed in early dividing cells from all three germ layers from embryonic to perinatal stages [10].
• Notably, high levels of WOX1 immunoreactivity was observed in the neural crest-derived structures such as cranial and spinal ganglia and cranial mesenchyme during the late fetal stage [10].
• In murine fetuses, WOX1 was present prevalently in the brainstem, spinal cord and peripheral nerve bundles, but its expression decreased after birth [10].
• In parallel, the expression of WOX1, as determined by Western blotting, was significantly reduced in the brain stem and spinal cord of adult mice [10].

Associations of Wwox with chemical compounds

• Alterations of tyrosine 33 in the first WW domain of Wwox or the proline-rich motif in AP-2gamma dramatically reduce this interaction [11].
• 17Beta-estradiol, a neuronal protective hormone, increased the binding of WOX1 and GSK-3beta with Tau [4].
• By stimulating cells with anisomycin or UV light, JNK1 became activated, and WOX1 was phosphorylated at Tyr(33) [12].

Co-localisations of Wwox

• Also, WOX1 colocalized with fragments of opsin-positive cones [9].

Other interactions of Wwox

• PH-20 sensitizes various cancer cells to tumor necrosis factor (TNF) cytotoxicity by upregulating proapoptotic p53 and WW domain-containing oxidoreductase (WOX1) [13].
• Here, the potential role of WOX1 in light-induced retinal degeneration in vivo was investigated [9].

Analytical, diagnostic and therapeutic context of Wwox

• Site-directed mutagenesis revealed that activated Ack1 primarily phosphorylated Wwox at Tyr287, suggesting that phosphorylation of distinct tyrosine residues activate or degrade Wwox [5].
• By electron microscopy, a large number of immunogold particles of WOX1 and p-WOX1 were found in the damaged mitochondria and condensed nuclei of degenerating photoreceptors, indicating that WOX1 undergoes activation and translocation to these organelles [9].
• The activated JNK1 physically interacted with the phosphorylated WOX1, as determined by co-immunoprecipitation [12].

References