Competitive binding of AUF1 and TIAR to MYC mRNA controls its translation

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Abstract

(A+U)-rich elements (AREs) within 3′ untranslated regions are signals for rapid degradation of messenger RNAs encoding many oncoproteins and cytokines. The ARE-binding protein AUF1 contributes to their degradation. We identified MYC proto-oncogene mRNA as a cellular AUF1 target. Levels of MYC translation and cell proliferation were proportional to AUF1 abundance but inversely proportional to the abundance of the ARE-binding protein TIAR, a MYC translational suppressor. Both AUF1 and TIAR affected MYC translation via the ARE without affecting mRNA abundance. Altering association of one ARE-binding protein with MYC mRNA in vivo reciprocally affected mRNA association with the other protein. Finally, genetic experiments revealed that AUF1 and TIAR control proliferation by a MYC-dependent pathway. Together, these observations suggest a novel regulatory mechanism where tuning the ratios of AUF1 and TIAR bound to MYC mRNA permits dynamic control of MYC translation and cell proliferation.

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Figure 1: Effects of AUF1 abundance on MYC expression.
Figure 2: AUF1 affects translation via the MYC ARE.
Figure 3: AUF1 abundance affects polyribosome distribution of MYC mRNA.
Figure 4: Effects of AUF1 and TIAR on MYC expression and mRNA association.
Figure 5: Effects of AUF1 or TIAR overexpression on ARE association.
Figure 6: AUF1 controls cellular proliferation.
Figure 7: Model for AUF1 control of MYC translation.

Change history

  • 21 May 2007

    fixed y axis of figure 2b

Notes

  1. 1.

    *NOTE: In the version of this article initially published online, the y-axis label in Figure 2b is incorrect. The correct label should be Luc activity. The error has been corrected for all versions of the article.

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Acknowledgements

We thank M. Gorospe (National Institute on Aging, US National Institutes of Health) for providing TIAR siRNA and the polyribosome gradient procedure; M. Gorospe, N. Kedersha and P. Anderson (Harvard Medical School) for plasmids pMT2 and pMT2-HA-TIAR; J. Leon (Universidad de Cantabria) for cell lines KmycB and KmycJ; and S. Gross and T. Kinzy (Robert Wood Johnson Medical School) for technical assistance with the polyribosome gradient experiments. This work was supported by US National Institutes of Health grant CA052443 to G.B.

Author information

B.L. designed and performed experiments, interpreted experimental data and wrote the paper. Y.H. performed experiments. G.B. designed experiments, interpreted experimental data and wrote the paper. All authors approved the final version of the paper.

Correspondence to Gary Brewer.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Antibody specific for AUF1 precipitates MYC mRNA from cytoplasmic lysates of K562 cells (PDF 68 kb)

Supplementary Fig. 2

Effects of AUF1 knockdown on MYC gene expression in HeLa cells (PDF 3620 kb)

Supplementary Fig. 3

Effects of AUF1 knockdown on luciferase-MYC ARE reporter gene expression in HeLa cells (PDF 799 kb)

Supplementary Fig. 4

TIAR antibody precipitates MYC ARE reporter mRNA but not luciferase mRNA lacking the ARE (PDF 720 kb)

Supplementary Fig. 5

TIAR knockdown has no effect on MYC mRNA levels in K562 cells (PDF 780 kb)

Supplementary Fig. 6

Effects of TIAR knockdown on luciferase–MYC ARE reporter gene expression with in K562 cells (PDF 822 kb)

Supplementary Fig. 7

Controls for mRNP immunoprecipitations following AUF1 and TIAR knockdown (PDF 833 kb)

Supplementary Fig. 8

AUF1 knockdown retards proliferation of HeLa cells (PDF 54 kb)

Supplementary Fig. 9

TIAR knockdown reverses the cellular proliferation defect conferred by AUF1 knockdown (PDF 55 kb)

Supplementary Fig. 10

MYC knockdown reverses the proliferation-inducing effects of TIAR knockdown (PDF 157 kb)

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Liao, B., Hu, Y. & Brewer, G. Competitive binding of AUF1 and TIAR to MYC mRNA controls its translation. Nat Struct Mol Biol 14, 511–518 (2007) doi:10.1038/nsmb1249

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