Candidate tumour suppressor Fau regulates apoptosis in human cells: an essential role for Bcl-G

FAU, which encodes a ubiquitin-like protein (termed FUBI) with ribosomal protein S30 as a carboxy-terminal extension, has recently been identified as a pro-apoptotic regulatory gene. This activity may be mediated by Bcl-G (a pro-apoptotic member of the Bcl-2 Family) which can be covalently modified by FUBI. FAU gene expression has been shown to be down-regulated in human breast, prostate and ovarian tumours, and this down-regulation is strongly associated with poor prognosis in breast Cancer. We demonstrate here that ectopic FAU expression increases basal Apoptosis in human T-cell lines and 293T/17 cells, whereas it has only a transient stimulatory effect on ultraviolet-C (UVC)-induced Apoptosis. Conversely, siRNA-mediated silencing of FAU gene expression has no effect on basal Apoptosis, but attenuates UV-induced Apoptosis. Importantly, prior knockdown of Bcl-G expression ablates the stimulation of basal Apoptosis by FAU, consistent with an essential downstream role for Bcl-G, itself a candidate tumour suppressor, in mediating the Apoptosis regulatory role of FAU. In 293T/17 cells, Bcl-G knockdown also attenuates UV-induced Apoptosis, so that Bcl-G may constitute a common factor in the pathways by which both FAU and UV-irradiation induce Apoptosis. UV irradiation increases Bcl-G mRNA levels, providing an explanation for the transient nature of the effect of ectopic FAU expression on UV-induced Apoptosis. Since failure of Apoptosis is fundamental to the development of many cancers, the pro-apoptotic activity of the Fau/Bcl-G pathway offers an attractive explanation for the putative tumour suppressor role of FAU.