The WWOX gene encodes a protein with two WW domains followed by a short-chain dehydrogenase domain that was identified from a genomic region 16q23 of high instability, FRA16D. The mouse homolog, termed Wox1, was found to enhance TNFα-mediated apoptosis. The WWOX gene is disrupted in a many cancer types by deletions or translocation which has revealed a tumor suppressor function. In contrast, high levels of WWOX have been shown in shown in premetastic cancers, including breast and prostate. Stress stimuli can induce tyrosine phosphorylation within the first WW domain, followed by nuclear translocation and binding to and stabilizing the p53 tumor suppressor protein. WWOX and p53 can induce apoptosis in a synergistic manner. Tyrosine phosphorylation and nuclear translocation of WWOX has been implicated in the progression of cancers to metastatic states.
[1] Bednarek, A.K. et al. (2000) Cancer Res. 60, 2140-2145.
[2] Ried, K. et al. (2000) Hum. Mol. Genet. 9, 1651-1663.
[3] Chang, N.S. et al. (2001) J. Biol. Chem. 276, 3361-3370.
[4] Ramos, D. and Aldaz, C.M. (2006) Adv. Exp. Med. Biol. 587, 149-159.
[5] Paige, A.J. et al. (2001) Proc. Nat.l Acad. Sci. USA 98, 11417-11422.
[6] Bednarek, A.K. et al. (2001) Cancer Res. 61, 8068-8073.
[7] Aqeilan, R.I. et al. (2007) Proc. Natl. Acad. Sci. USA 104, 3949-3954.
[8] Driouch, K. et al. (2002) Oncogene 21, 1832-1840.
[9] Watanabe, A. et al. (2003) Cancer Res. 63, 8629-8633.
[10] Chang, N.S. et al. (2005) Oncogene 24, 714-723.
