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.
Highlights
The PIM1 gene encodes a serine/threonine kinase that can regulate cell proliferation and survival at multiple levels [1,2]
In order to characterize molecular events contributing to transient accumulation of PIM1 mRNA, and to ascertain whether these mechanisms applied to nonhematopoietic cell types, it was first necessary to determine whether PIM1 mRNA was regulated by mitogenic stimulation in tractable cultured cell systems
We show that induction of PIM1 mRNA following mitogenic stimulation with serum+TPA is temporally limited in several cell models (Figure 1), and that rapid restoration to basal expression levels involves acceleration of mRNA decay in each case (Table 1)
Summary
The PIM1 gene encodes a serine/threonine kinase that can regulate cell proliferation and survival at multiple levels [1,2]. Pim-1-mediated phosphorylation of the tyrosine phosphatase Cdc25A increases its activity [3], which includes activation of Cdk2/cyclin E to promote progression from G1 into S phase [4]. In response to genotoxic stress, the cyclin-dependent kinase inhibitor p21waf/Cip blocks DNA replication by binding to proliferating cell nuclear antigen (PCNA) [5]; phosphorylation of p21 by Pim-1 disrupts the p21-PCNA complex, stimulating resumption of S phase [6]. While phosphorylation of Cdc25C by its associated kinase C-TAK1 blocks the ability of Cdc25C to activate the G2/M switch, phosphorylation of C-TAK1 by Pim-1 abrogates this checkpoint activity [7]. Pim-1 phosphorylation events promote recruitment of nuclear mitotic factors to spindle poles, an essential event in cell division [8]. Pim-1 can suppress programmed cell death by inactivating the pro-apoptotic proteins Bad [9] and ASK1 [10]
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