P38 regulates the tumor suppressor PDCD4 via the TSC-mTORC1 pathway.

Clarissa Braun,Karl Katholnig,Christopher Kaltenecker,Nyamdelger Sukhbaatar,Monika Linke,Markus Hengstschläger,Thomas Weichhart

doi:10.15698/cst2021.12.260

Clarissa Braun, Karl Katholnig + Show 5 more

Open Access

https://doi.org/10.15698/cst2021.12.260

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Journal: Cell stress	Publication Date: Dec 13, 2021
Citations: 5	License type: cc-by

Affiliation: Medical University of Vienna

Abstract

Programmed cell death protein 4 (PDCD4) exerts critical functions as tumor suppressor and in immune cells to regulate inflammatory processes. The phosphoinositide 3-kinase (PI3K) promotes degradation of PDCD4 via mammalian target of rapamycin complex 1 (mTORC1). However, additional pathways that may regulate PDCD4 expression are largely ill-defined. In this study, we have found that activation of the mitogen-activated protein kinase p38 promoted degradation of PDCD4 in macrophages and fibroblasts. Mechanistically, we identified a pathway from p38 and its substrate MAP kinase-activated protein kinase 2 (MK2) to the tuberous sclerosis complex (TSC) to regulate mTORC1-dependent degradation of PDCD4. Moreover, we provide evidence that TSC1 and TSC2 regulate PDCD4 expression via an additional mechanism independent of mTORC1. These novel data extend our knowledge of how PDCD4 expression is regulated by stress- and nutrient-sensing pathways.

Highlights

Programmed cell death protein 4 (PDCD4) is an RNAbinding tumor suppressor protein that is vital for inhibiting carcinogenesis, tumor progression and invasion [1]
In bone marrow-derived macrophages (BMDMs) we found that LPS and anisomycin induced the reduction of programmed cell death protein 4 (PDCD4) (Fig. 1A)
Our data suggests that p38 induces degradation of PDCD4 via mammalian target of rapamycin complex 1 (mTORC1) and TSC1/tuberous sclerosis complex 2 (TSC2)

Summary

INTRODUCTION

Programmed cell death protein 4 (PDCD4) is an RNAbinding tumor suppressor protein that is vital for inhibiting carcinogenesis, tumor progression and invasion [1]. Inhibition of p38 or mTORC1 prevented anisomycin-induced degradation of PDCD4 in Tsc1+/+ and Tsc2+/+ fibroblasts (Fig. 2C and D) and in Tsc2fl/fl BMDMs stimulated with anisomycin or LPS (Fig. 2E and F). BIRB796 failed to rescue PDCD4 degradation in anisomycin-stimulated Tsc1-/- and Tsc2-/- fibroblasts (Fig. 2C and D) and in Tsc2Lyz BMDMs (Fig. 2E) These results show that p38 controls PDCD4 expression via TSC1/TSC2. Rapamycin and the catalytic mTOR inhibitor Torin partially restored PDCD4 levels in anisomycin-stimulated Tsc1-/- and Tsc2-/- fibroblasts (Fig. 2C and D). We noticed that the proteasome inhibitor MG-132 restored PDCD4 levels in anisomycin-treated Tsc1+/+ and Tsc2+/+ fibroblasts as well as anisomycin- and LPS-stimulated BMDMs (Fig. 3A, 2D-F). In Tsc1-/- and Tsc2-/- fibroblasts as well as Tsc2Lyz BMDMs, MG-132 could not fully restore PDCD4 levels arguing again of an TSC1/TSC2-dependent effect that is independent of mTORC1 and proteasomal degradation (Fig. 3A, 2D-F). Treating BMDMs with the p38-activating translation elongation inhibitor cycloheximide (Chx) [23, 24] confirmed that PDCD4 translation is under strong control of this MAPK (Fig. 3B)

DISCUSSION

MATERIALS AND METHODS