Altered dynamics of ubiquitin hybrid proteins during tumor cell apoptosis

Abstract

The ubiquitin hybrid genes Uba80 and Uba52 encode ubiquitin (Ub), which is fused to the ribosomal proteins S27a (RPS27a) and L40 (RPL40), respectively. Here, we show that these genes are preferentially over-expressed during hepatoma cell apoptosis. Experiments using the tet-inducible transgenic system revealed that over-expression of the ubiquitin hybrid genes sensitized the cells to apoptosis. Further analysis suggested that Ub, and not RPS27a or RPL40, was associated with apoptotic cell death. Cleavage-resistant mutation analysis revealed that the N-terminal portion and the last two amino acids (GG) of Ub are critical for cleavage at the junction between the two protein moieties. An apoptogenic stimulus enhances the nuclear targeting and aggregation of Ub in the nucleus, resulting in histone H2A deubiquitylation followed by abnormal ubiquitylation of the nuclear envelope and the lamina. These events accompany the apoptotic nuclear morphology in the late stage of apoptosis. Each fused RP is localized in the nucleoli. These results suggest a role for Ub hybrid proteins in the altered nuclear dynamics of Ub during tumor cell apoptosis induced by apoptogenic stimuli.

Proteins that mediate protein aggregation and cytotoxicity distinguish Alzheimer's hippocampus from normal controls

“…Vinculin is one of three extracellular matrix protein hubs in a protein‐interaction network of ‘age‐related disease proteins’ (Wolfson et al ., 2009). Ubiquitin hybrid (fusion) genes, Uba52 and Uba80, encode ubiquitin fused to ribosomal proteins and are upregulated during tumor‐cell apoptosis (Han et al ., 2012). …”

Dynamic transcription of ubiquitin genes under basal and stressful conditions and new insights into the multiple UBC transcript variants

“…From a biological point of view, this means that UV-C light acts at the posttranscriptional level, through the stabilization of Ub mRNAs, as a strategy for cells to face the increased ubiquitin demand. This is not quite surprising since Han et al reported that various apoptogenic stimuli induce the Ub-ribosomal fusion proteins by stabilizing their mRNAs, rather than by transcriptional induction of their encoding genes (Han et al, 2012). Thus, it can be hypothesized that UV challenge causes genotoxic injuries which in turn trigger different DNA damage response pathways: most of them rely on ubiquitination of specific protein targets, that change depending on genomic location and time within the cell cycle (Bergink et al, 2007).…”

Involvement of ubiquitin-coding genes in cadmium-induced protein ubiquitination in human proximal tubular cells

“…UBB and UBC encode 3 and 9 tandem polyUbs, respectively (Baker and Board, 1987;Oh et al, 2013). UBA52 and UBA80 encode Ub fusion proteins characterized by differences in the protein tail lengths, 52-and 80-amino-acids, respectively (Baker and Board, 1991;Han et al, 2012). Ub protein levels are tightly controlled in cells (Vabulas, 2007).…”