TRB3 protects cells against the growth inhibitory and cytotoxic effect of ATF4

Palmitate Induces TRB3 Expression and Promotes Apoptosis in Human Liver Cells

“…Thus, we hypothesized that saturated fatty acids augment TRB3 expression under conditions of ER stress and lead to apoptosis in human liver cells. It has previously been shown that the effect of TRB3 on survival or apoptosis are dependent on the cell type and context [18,23,30,31,32,33,34]. Here, we have demonstrated for the first time that TRB3 is significantly increased at the protein and mRNA level during palmitate-induced ER stress in the normal human liver cell line, L02, and that this higher expression level is associated with increased apoptosis.…”

“…Tribbles homolog 3 (TRB3, also known as NIPK, SKIP3, TRIB3 and SINK) is a pseudokinase that modulates many signaling cascades associated with ER stress, nutrient deficiency, insulin resistance, hypoxia and the regulation of cell growth and differentiation [17,18,19,20,21]. Ohoka and colleagues reported that TRB3 is expressed in the human hepatoma cell line HepG2, and its expression level was increased during tunicamycin-induced ER stress [22].…”

Human TRB3 is upregulated in stressed cells by the induction of translationally efficient mRNA containing a truncated 5′-UTR

“…TRB3, which acts as a feedback inhibitor of ATF4 (Ohoka et al, 2005;Örd and Örd, 2005;Jousse et al, 2007;Örd et al, 2007), the key regulator of gene expression during the integrated stress response (Harding et al, 2003), is transcriptionally induced by a variety of stresses (Bowers et al, 2003;Örd and Örd, 2003;Corcoran et al, 2005;Schwarzer et al, 2006;Yacoub Wasef et al, 2006;Jousse et al, 2007;Su and Kilberg, 2008). We have previously demonstrated the existence of a number of human (h) TRB3 mRNA isoforms, all of which contain the same coding region, but differ in their 5′ regions immediately upstream of the hTRB3 translation start codon as a result of alternative transcription initiation and alternative splicing of the first exon (Örd and Örd, 2005).…”

MAPK signaling triggers transcriptional induction of cFOS during amino acid limitation of HepG2 cells

“…5E). The HEK293T-ATF4 cell line used for these studies had been previously transfected to stably express ATF4 under the control of tetracycline (TET) [28]. Treatment of these cells with TET to induce ATF4 leads to an induction of ATF4-responsive genes such as ASNS and CHOP [37].…”

“…For stable knock down studies, HepG2 cells transduced with lentivirus constructs were plated at a density of 2.5 × 10 5 cells per 60 mm dish to permit shRNA expression and then treated with DMEM or DMEM-His at a similar confluence as the cells in all other experiments. The HEK293T-ATF4 cell line (with tetracycline (TET)-inducible ATF4 expression) was a gift from Dr. Tonis Ord [28], (Institute of Molecular and Cell Biology, Tartu University, Tartu, Estonia). The HEK293T-ATF4 cells were stably transfected at 5 μg/60 mm dish with a constitutively-active MEK1 (MEK CA ) construct [29] or as a control, green fluorescent protein (GFP-pcDNA3.1), using a calcium phosphate protocol [30].…”