Journal of Biological Chemistry
Volume 288, Issue 32, 9 August 2013, Pages 23161-23170
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Gene Regulation
Methionine Adenosyltransferase 2B, HuR, and Sirtuin 1 Protein Cross-talk Impacts on the Effect of Resveratrol on Apoptosis and Growth in Liver Cancer Cells*

https://doi.org/10.1074/jbc.M113.487157Get rights and content
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Resveratrol is growth-suppressive and pro-apoptotic in liver cancer cells. Methionine adenosyltransferase 2B (MAT2B) encodes for two dominant variants V1 and V2 that positively regulate growth, and V1 is anti-apoptotic when overexpressed. Interestingly, crystal structure analysis of MAT2B protein (MATβ) protomer revealed two resveratrol binding pockets, which raises the question of the role of MAT2B in resveratrol biological activities. We found that resveratrol induced the expression of MAT2BV1 and V2 in a time- and dose-dependent manner by increasing transcription, mRNA, and protein stabilization. Following resveratrol treatment, HuR expression increased first, followed by SIRT1 and MAT2B. SIRT1 induction contributes to increased MAT2B transcription whereas HuR induction increased MAT2B mRNA stability. MATβ interacts with HuR and SIRT1, and resveratrol treatment enhanced these interactions while reducing the interaction between MATβ and MATα2. Because MATβ lowers the Ki of MATα2 for S-adenosylmethionine (AdoMet), this allowed steady-state AdoMet level to rise. Interaction among MATβ, SIRT1, and HuR increased stability of these proteins. Induction of MAT2B is a compensatory response to resveratrol as knocking down MAT2BV1 potentiated the resveratrol pro-apoptotic and growth-suppressive effects, whereas the opposite occurred with V1 overexpression. The same effect on growth occurred with MAT2BV2. In conclusion, resveratrol induces HuR, SIRT1, and MAT2B expression; the last may represent a compensatory response against apoptosis and growth inhibition. However, MATβ induction also facilitates SIRT1 activation, as the interaction stabilizes SIRT1. This complex interplay among MATβ, HuR, and SIRT1 has not been previously reported and suggests that these proteins may regulate each other's signaling.

Background: Methionine adenosyltransferase 2B protein (MATβ) binds to resveratrol, but it exerts the opposite effects on growth and apoptosis.

Results: Resveratrol induces HuR, SIRT1, and MATβ expression. These proteins interact, which stabilizes them. MATβ induction blunts the resveratrol effect on growth and apoptosis.

Conclusion: MATβ-HuR-SIRT1 interaction impacts resveratrol actions.

Significance: This is the first demonstration of MATβ in SIRT1 signaling.

Apoptosis
Cell Growth
Liver Cancer
Resveratrol
Sirt1
HuR
Methionine Adenosyltransferase 2B

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*

This work was supported, in whole or in part, by National Institutes of Health Grant R01DK51719 (to S. C. L., H. Y., and J. M. M.). This work was also supported by Plan Nacional of I+D SAF 2011-29851 (to J. M. M.), ETORTEK-2011, Sanidad Gobierno Vasco 2008, Educación Gobierno Vasco 2011 (PI2011/29), and Fondo de Investigacion Sanitaria (PI11/01588) (to M. L. M.-C.). Huh7 and HepG2 cells were provided by the Cell Culture Core of the University of Southern California Research Center for Liver Diseases under Grant P30DK48522.

1

Both authors share first authorship.