Coordinated Expression of Tristetraprolin Post-Transcriptionally Attenuates Mitogenic Induction of the Oncogenic Ser/Thr Kinase Pim-1

Abstract

The serine/threonine kinase Pim-1 directs selected signaling events that promote cell growth and survival and is overexpressed in diverse human cancers. Pim-1 expression is tightly controlled through multiple mechanisms, including regulation of mRNA turnover. In several cultured cell models, mitogenic stimulation rapidly induced and stabilized PIM1 mRNA, however, vigorous destabilization 4–6 hours later helped restore basal expression levels. Acceleration of PIM1 mRNA turnover coincided with accumulation of tristetraprolin (TTP), an mRNA-destabilizing protein that targets transcripts containing AU-rich elements. TTP binds PIM1 mRNA in cells, and suppresses its expression by accelerating mRNA decay. Reporter mRNA decay assays localized the TTP-regulated mRNA decay element to a discrete AU-rich sequence in the distal 3′-untranslated region that binds TTP. These data suggest that coordinated stimulation of TTP and PIM1 expression limits the magnitude and duration of PIM1 mRNA accumulation by accelerating its degradation as TTP protein levels increase. Consistent with this model, PIM1 and TTP mRNA levels were well correlated across selected human tissue panels, and PIM1 mRNA was induced to significantly higher levels in mitogen-stimulated fibroblasts from TTP-deficient mice. Together, these data support a model whereby induction of TTP mediates a negative feedback circuit to limit expression of selected mitogen-activated genes.

PIM2 interacts with tristetraprolin and promotes breast cancer tumorigenesis

“…Previous studies reported that TTP regulated the mRNA decay of PIM1 and PIM3 but not that of PIM2 (Kim et al ., ; Mahat et al ., ; Selmi et al ., ). Our study showed a negative feedback loop between PIM family proteins and TTP through the PIM2‐degradation of TTP.…”

miR‐29a inhibition normalizes HuR over‐expression and aberrant AU‐rich mRNA stability in invasive cancer

“…We previously found that TTP restoration in MDA-MB-231 cells promotes the decay of uPA and uPAR, resulting in a decrease in the invasive capacity of these cells [1]. TTP also has multiple important targets, including COX-2, HIF-1α, IL-8, IL-6, IL-8, and VEGF [34,[36][37][38][39][40] and the oncogenic Ser/Th kinase Pim-1, which is overexpressed in several cancers and promotes cellular growth and apoptosis resistance [41,42]. Thus, TTP appears to be a down-regulator of many cancer-related genes, which substantiates its anti-tumour role.…”

Hallmarks of cancer and AU‐rich elements

“…In cancer cells, pim-1 mRNA has been shown to be functionally correlated with TTP expression in several cell lines and tumor tissues. 112 Pim-1 kinase phosphorylates different substrates, including Myc, p21/ Cip1/ WAF1, and p27K, and thus regulates cell cycle progression. TTP-induced reduction of Pim-1 thus leads to a decrease in the phosphorylation of p21 and p27; in turn, TTP deficiency can result in increased tumor cell growth.…”