Aberrant ribosome biogenesis activates c-Myc and ASK1 pathways resulting in p53-dependent G1 arrest

Abstract

The largest energy consumer in the cell is the ribosome biogenesis whose aberrancy elicits various diseases in humans. It has been recently revealed that p53 induction, along with cell cycle arrest, is related with abnormal ribosome biogenesis, but the exact mechanism still remains unknown. In this study, we have found that aberrant ribosome biogenesis activates two parallel cellular pathways, c-Myc and ASK1/p38, which result in p53 induction and G1 arrest. The c-Myc stabilizes p53 by rpL11-mediated HDM2 inhibition, and ASK1/p38 activates p53 by phosphorylation on serine 15 and 33. Our studies demonstrate the relationship between these two pathways and p53 induction. The changes caused by impaired ribosomal stress, such as p53 induction and G1 arrest, were completely disappeared by inhibition of either pathway. These findings suggest a monitoring mechanism of c-Myc and ASK1/p38 against abnormal ribosome biogenesis through controlling the stability and activity of p53 protein.

5-Fluorouracil signaling through a calcium–calmodulin-dependent pathway is required for p53 activation and apoptosis in colon carcinoma cells

“…As inhibition of p38MAPKa by the SB203580 compound or by short hairpin RNA interference obstructed 5-FU-associated apoptosis while autophagy was promoted, p38MAPK was suggested to act as a potential regulator of p53 and the balance between apoptotic and autophagic processes. 32 In turn, the mammalian mitogen-activated protein (MAP3K) apoptosis signalregulating kinase 1 (ASK1) is a pivotal component in cytokine-and stress-induced apoptosis, which may act as a critical intermediate of Ca 2 þ signaling between Ca 2 þ -CaM-dependent protein kinase type II and p38MAPK 33,34 It is, therefore, possible that the Ca 2 þ -dependent apoptotic pathway disclosed by our data merges with the previously defined p38MAPK pathway. 32 To verify this hypothesis, 5-FU-treated HCT116 cells were pre-incubated with BAPTA and the p38MAPKa inhibitor SB203580, either separately or in combination (Figure 7).…”

“…1,4,38 Although DNA lesion represent the most well-documented incident causing activation of p53, recent reports also involve transcriptional stress and ribosome damage in signaling events, leading to specific posttranslational modifications of the tumor suppressor. 5,34 An accumulation of double-strand breaks in response to 5-FU in HCT116 cells is evident as the number of gH2AX foci observed by immunostaining increased over time (data not shown), but our data involving ATM inhibition by KU55933 and Chk2-deficient cells excluded the DNA damage response as a starting point for Ca 2 þ -induced p53 phospho activation. Thereby, we are not arguing that apoptosis proceed irrespectively of the DNA damage response.…”

Characterization of genomic imbalances in diffuse large B‐cell lymphoma by detailed SNP‐chip analysis

“…Both genes show a significantly reduced expression in cases with deletion at this position. MAP3K5 is a kinase that participates in signaling pathways leading to apoptosis or senescence via p53 and was so far not described as being downregulated in DLBCL. TNFAIP3 encodes for A20, a negative regulator of NF‐κB signaling that is often inactivated in ABC‐DLBCLs via mutation and/or deletion .…”

p53 as an intervention target for cancer and aging

“…Ribosomal stress induces apoptosis that depends on both rpL11 and p53 in mouse pluripotent stem cells (80). In addition, the oncoprotein c-Myc stabilizes p53 through rpL11-mediated HDM2 (the human ortholog to MDM2) inhibition, and the ASK1/p38 kinase activates p53 through phosphorylation on serine 15 and 33 (81). However, rp5, rpL11, and rp23 are needed to stabilize p53, not serine 15 phosphorylation (82,83).…”