Abstract
The WWOX tumor suppressor is a WW domain-containing protein. Its function in the cell has been shown to be mediated, in part, by interacting with its partners through its first WW (WW1) domain. Here, we demonstrated that WWOX via WW1 domain interacts with p53 homolog, ΔNp63α. This protein–protein interaction stabilizes ΔNp63α, through antagonizing function of the E3 ubiquitin ligase ITCH, inhibits nuclear translocation of ΔNp63α into the nucleus and suppresses ΔNp63α transactivation function. Additionally, we found that this functional crosstalk reverses cancer cells resistance to cisplatin, mediated by ΔNp63α, and consequently renders these cells more sensitive to undergo apoptosis. These findings suggest a functional crosstalk between WWOX and ΔNp63α in tumorigenesis.
Highlights
The gene spans the fragile site FRA16D that includes a genomic region involved in chromosome translocation in multiple myelomas and in hemi- and homozygous deletions in cancers and cancer-derived cell lines; in addition, the WW domain-containing oxidoreductase (WWOX) promoter region is frequently hypermethylated in cancers.[3,4] Wwox-knockout mice demonstrated that WWOX functions as a bona fide tumor suppressor
In previous work,[21] we reported that WWOX physically and functionally interacts via its WW1 domain with the p53 homolog, p73 through its PPxY motif
The results revealed that WWOX binds to DNp63a as determined by immunoprecipitation with anti-Myc and IB with anti-HA antibody (Figure 1a, upper panel, lane 7), while it failed to do so with TAp63a (Figure 1a, upper panel, lane 4)
Summary
The gene spans the fragile site FRA16D that includes a genomic region involved in chromosome translocation in multiple myelomas and in hemi- and homozygous deletions in cancers and cancer-derived cell lines; in addition, the WWOX promoter region is frequently hypermethylated in cancers.[3,4] Wwox-knockout mice demonstrated that WWOX functions as a bona fide tumor suppressor. Whereas the TAp63 proteins are capable of transactivation, the DNp63 forms can act in a dominant-negative fashion to counteract the transcriptional activity of the TAp63 isoforms and p53.9,10 This isoform is highly expressed in basal or reserve cells, immature squamous epithelium, and epithelial stem cells. Both DNp63 and TAp63 can be subdivided further into three unique C-terminal sequence variants, conveniently designated as a, b, and g, yielding a total of six discrete p63 gene products.
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