Tumor Suppressor PDCD4 Represses Internal Ribosome Entry Site-Mediated Translation of Antiapoptotic Proteins and Is Regulated by S6 Kinase 2

Abstract

A poptosis, or programmed cell death, is important for the normal development of organisms and maintaining tissue homeostasis. Misregulation of apoptosis may lead to neurodegenerative disorders when apoptosis is increased and tumor formation when apoptosis is inhibited; thus, the pathway is tightly controlled, with both pro-and antiapoptotic factors playing a role. Of particular interest are members of the inhibitor of apoptosis (IAP) and Bcl-2 families of proteins that intercept virtually all apoptotic signals in the cell.X chromosome-linked inhibitor of apoptosis (XIAP) is the most potent member of the IAP family; it directly interacts with and inhibits caspases 3, 7, and 9 and is therefore a key regulator of apoptosis (20). In contrast, Bcl-x L controls apoptosis by maintaining mitochondrial membrane homeostasis (14). Interestingly, both the XIAP and Bcl-x L mRNAs contain an internal ribosome entry site (IRES) that allows them to be translated during cellular stress by a cap-independent mechanism when cap-dependent translation is inhibited, which is necessary for their protective roles in the cell (4,11,16,24,49). Under normal growth conditions, translation of cellular mRNAs occurs through a cap-dependent mechanism that requires interaction of specific initiation factors (such as eukaryotic initiation factor 4E [eIF4E]) with the 5= cap of the mRNA, followed by recruitment of ribosomal subunits, recognition of the AUG start codon, and commencement of polypeptide chain elongation (reviewed in reference 26). However, certain cellular stresses such as nutrient deprivation, hypoxia, or low-dose irradiation cause attenuation of cap-dependent translation, and yet, under these conditions, a sizeable proportion of cellular mRNAs, perhaps as much as 10%, have been shown to be translated by a cap-independent mechanism, such as through an IRES (23,28,39). IRES elements are located within the 5= untranslated region (UTR) of some cellular mRNAs and are believed to recruit the ribosome directly, thereby bypassing the requirement for the mRNA 5= cap and eIF4E. Moreover, while IRES-dependent translation requires some canonical translation initiation factors, most (if not all) cellular IRES elements require the activity of auxiliary RNA binding proteins that function as IRES trans-acting factors (ITAFs) (reviewed in references 28 and 32). The mechanism by which ITAFs function is poorly understood, and since different IRESs require different sets of ITAFs, elucidating the identity of all known ITAFs has proven challenging. Furthermore, it has been shown that ITAFs can function as either positive or negative regulators of IRES-mediated translation. For example, heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) was shown to act as a repressor of XIAP IRES-mediated translation (33), whereas La autoantigen (19), hnRNPC1 and hnRNPC2 (18), and HuR (11) have all been shown to have a stimulating effect on XIAP IRES-mediated translation.We have previously demonstrated that treatment of small-cell lung cancer cells with fibroblast gr...

STAT1 Promotes KRAS Colon Tumor Growth and Susceptibility to Pharmacological Inhibition of Translation Initiation Factor eIF4A

“…The prosurvival properties of STAT1 are mediated, at least in part, by the downregulation of PDCD4 and increased eIF4A activity, leading to increased translation of XIAP and BCL-XL mRNAs. This is in line with other studies demonstrating the important role of PDCD4 in the translational repression of XIAP and BCL-XL mRNAs in different human tumors via cap-independent mechanisms (30,31). The translational effects of STAT1 occur in HCT116 cells but not in HK2-8 cells, suggesting their dependency on activated KRAS.…”

Dicer1 imparts essential survival cues in Notch-driven T-ALL via miR-21–mediated tumor suppressor Pdcd4 repression

“…Recent structural studies on PDCD4 revealed that it inhibits initiation of cap-dependent protein translation by binding to the RNA helicase elongation initiation factor 4A (eIF4A) and the scaffold protein elF4G 65 or by blocking internal ribosomal entry site-mediated translation of the prosurvival genes Bcl-XL and Xiap. 42 Interestingly, our correlative studies on BCL-xL protein levels in murine and human T-ALL cell lines confirms that miR-21 is regulating BCL-xL through the repression of Pdcd4.…”

“…Simultaneous KD of miR-21 and Pdcd4 rescued to a large extent the miR-21 KD-induced apoptotic phenotype in T-ALL cell lines ( Figure 6F-G and supplemental Figure 8E). Pdcd4 has been proposed to act at least in part through translational inhibition of BCL-xL, 39,42 which has been implicated in the survival of human T-ALL lines and primary tumors. 43 Interestingly, BCL-xL protein levels were downregulated in miR-21 KD T-ALL cells and increased in cells in which miR-21 and Pdcd4 were knocked down simultaneously (supplemental Figure 8F).…”

MicroRNA-21 Aggravates Cyst Growth in a Model of Polycystic Kidney Disease

“…Programmed cell death 4 (Pdcd4) is a direct target of miR-21 and a novel tumor suppressor that promotes apoptosis. [20][21][22][23][24][25] Pdcd4 2/2 mice are born in normal Mendelian ratios and do not exhibit any overt pathology for the first few months of life. However, by approximately 80 weeks, these mice develop abdominal masses, which have been characterized as lymphoma of primary B cell origin.…”