Endoplasmic Reticulum Stress Induces G2 Cell-Cycle Arrest via mRNA Translation of the p53 Isoform p53/47

Abstract

p53 downstream pathways control G1 and G2 cell-cycle arrest, DNA repair, or apoptosis. However, it is still not clear how cells differentiate the cell-biological outcome of p53 activation in response to different types of stresses. The p53/47 isoform lacks the first 39 amino acids of full-length p53 including the Mdm2 binding site and the first trans-activation domain, and tetramers including p53/47 exhibit altered activity and biochemical properties. Here we show that endoplasmic reticulum stress promotes PERK-dependent induction of p53/47 mRNA translation and p53/47 homo-oligomerization. p53/47 induces 14-3-3sigma and G2 arrest but does not affect G1 progression. This is contrary to p53FL, which promotes G1 arrest but has no effect on the G2. These results show a unique role for p53/47 in the p53 pathway and illustrate how a cellular stress leads to a defined cell-biological outcome through expression of a p53 isoform.

Reversible induction of translational isoforms of p53 in glucose deprivation

“…14-3-3σ was recently reported as a preferential Δ40p53 target gene. 5,14 Expressing Δ40p53 from the 14A-M2 plasmid resulted in a 70% increase in 14-3-3σ mRNA in H1299-NS cells (Figure 2e). However, SMAR1 knockdown greatly compromised the induction of 14-3-3σ mRNA with only about 17% increase in the H1299-S3 cells, suggesting that SMAR1 is required for Δ40p53-mediated transactivation ( Figure 2e).…”

“…37,38,[50][51][52][53][54] Our recent study showed that SMAR1 is directly linked to translation of both p53 and Δ40p53 in normal as well as glucose-deprived conditions.14-3-3σ was demonstrated as a preferential transcriptional target of Δ40p53. 5,14 The downstream effects of Δ40p53 induction on target gene activation, and the resulting biological outcome, have been previously explored. [55][56][57] In the current study, using Δ40p53-mediated transactivation as a model, we showed that SMAR1 is important for IRESdependent Δ40p53 induction, as well as for the consequent elevation of 14-3-3σ mRNA (Figure 2e).…”

“…1 p53 and its N-terminally truncated isoform Δ40p53 (also known as ΔN-p53 or p53/47) are translated by internal ribosome entry site (IRES)-mediated translation initiation from the same mRNA under different stress conditions that induce DNA damage, ionizing radiation and endoplasmic reticulum (ER) stress, oncogene-induced senescence and cancer. [2][3][4][5][6][7] Thus, p53 mRNA has a dual IRES structure. 8 For their function, these IRESs rely on IRES trans-acting factors (ITAFs).…”

p53 isoforms gain functions

“…The suppression of PERK activity, 14-3-3s expression or deletion of the ER stress response IRES of p53/47 all result in an inhibition of UPR-induced G2/ M arrest. Together, this suggests that although p53/47 activates 14-3-3s, it also suppresses the induction of p21 CDKN1A/Cip1 and, thus, prevents the cells from arresting in G1/S while favouring a G2/M block (Bourougaa et al, 2010). In addition, expression of full-length p53 (p53FL) alone does not induce G2 arrest, but induces only GI arrest.…”

“…Further work showed that suppression of PERK activity, through overexpression of either a dominant-negative PERK or small interfering RNA, resulted in the suppression of p53/47 expression, indicating that PERK is the signal transducer between the ER and p53/47 expression ( Figure 2) (Bourougaa et al, 2010).…”