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  • Original Article
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Tristetraprolin regulates Cyclin D1 and c-Myc mRNA stability in response to rapamycin in an Akt-dependent manner via p38 MAPK signaling

Oncogene volume 25, pages 6277–6290 (2006)Cite this article

Abstract

The differential expression of the critical cell cycle control proteins cyclin D1 and c-myc has been shown to result in Akt-dependent hypersensitivity of tumor cells to mTOR inhibitors. We have previously demonstrated that the differential utilization of internal ribosome entry sites within the mRNAs of these transcripts allows maintenance of protein synthesis in the face of rapamycin (rapa) exposure in an Akt-dependent manner. Here, we demonstrate that in addition to this mechanism, cyclin D1 and c-myc mRNA stability is also coordinately regulated following rapa treatment depending on Akt activity status. We identify A/U-rich response elements within the 3′ untranslated regions (UTRs) of these transcripts, which confer the observed differential stabilities and show that the RNA-binding protein, tristetraprolin (TTP), interacts with these elements. We also present evidence that TTP accumulates in response to rapa exposure, binds to the cis-acting elements within the cyclin D1 and c-myc 3′ UTRs and is differentially serine phosphorylated in an Akt-dependent manner. Furthermore, the differential phosphorylation status of TTP results in its sequestration by 14-3-3 proteins in quiescent Akt-containing cells. Finally, siRNA-mediated knockdown of TTP expression or inhibiting a known regulator of TTP phosphorylation, p38 MAP kinase, abolishes the effects on cyclin D1 and c-myc mRNA stability. We assume that the differential control of cyclin D1 and c-myc mRNA stability and translational efficiency constitutes a coordinate response to rapa contributing to the maintenance of expression of these determinants in rapa-resistant quiescent Akt-containing cells following exposure.

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Accession codes

Accessions

GenBank/EMBL/DDBJ

Abbreviations

ORF:

open reading frame

TTP:

tristetraprolin

Akt:

Akt/protein kinase B

mTOR:

mammalian target of rapamycin

UTR:

untranslated region

MEF:

mouse embryonic fibroblast

MAPK:

mitogen activated protein kinase

PTEN:

phosphatase and tensin homolog deleted on chromosome 10

ActD:

actinomycin D

LPS:

lipopolysaccharide

rapa:

rapamycin

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Acknowledgements

We thank Dr Myriam Gorospe for providing luciferase/cyclin D1 3′ UTR constructs, Dr William Rigby for providing the CARP-3 antibody and Dr Andrew Clark for the GST-TTP construct. We also thank Drs Ingo Mellinghoff, Charles Sawyers and Hong Wu for providing cell lines. We are grateful to Drs Alan Lichtenstein and Matthew Rettig for helpful discussions and critical reading of the manuscript. This work was supported by funds from the Veterans Administration, a grant from the American Brain Tumor Association and NIH R01-CA109312.

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Authors and Affiliations

  1. Department of Research & Development, Greater Los Angeles Veterans Affairs Healthcare System, Sepulveda, CA, USA

    M Marderosian, A Sharma, A P Funk, R Vartanian, J Masri, O D Jo & J F Gera

  2. Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA

    J F Gera

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  1. M Marderosian
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Correspondence to J F Gera.

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Marderosian, M., Sharma, A., Funk, A. et al. Tristetraprolin regulates Cyclin D1 and c-Myc mRNA stability in response to rapamycin in an Akt-dependent manner via p38 MAPK signaling. Oncogene 25, 6277–6290 (2006). https://doi.org/10.1038/sj.onc.1209645

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