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Ribonucleotide reductase small subunit p53R2 suppresses MEK–ERK activity by binding to ERK kinase 2

Oncogene volume 28, pages 2173–2184 (2009)Cite this article

Abstract

The p53-dependent RR small subunit (p53R2) protein, a newly identified member of the ribonucleotide reductase family, plays a key role in the p53-dependent cellular response to DNA. Several recent studies have suggested that p53R2 also plays an important role in suppressing the invasive potential of human cancer cells. However, the cellular mechanism that regulates invasiveness remains largely unknown. In this study, we show that p53R2 interacts with MEK2 (extracellular signal-regulated kinase (ERK) kinase 2–mitogen-activated protein kinase (MAPK) kinase 2), the molecule immediately upstream of ERK in the Ras–Raf–MAPK signaling cascade. In co-immunoprecipitation and immunofluorescence analyses, we found that p53R2 and MEK2 interact physically in cultured mammalian cells, and that the p53R2 segment comprising amino acids 161–206 is critical for this interaction. Moreover, serum-induced phosphorylation of MEK1/2 and ERK1/2 was greatly augmented in human cancer cells expressing small-interfering RNA against p53R2. On the other hand, phosphorylation of MEK1/2 and ERK1/2 in human cancer cells was markedly attenuated by overexpression of p53R2. Furthermore, MEK2 was required for p53R2 knockdown-induced enhancement of the invasive ability and anchorage-independent growth of human lung cancer H1299 cells. Taken together, these findings show that p53R2 negatively modulates serum-induced MEK–ERK activity and inhibits the MEK–ERK-mediated malignancy potential of human cancer cells.

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Abbreviations

dNTP:

deoxyribonucleoside triphosphate

ERK:

extracellular signal-regulated kinase

MAPK:

mitogen-activated protein kinase

MEK2:

ERK kinase 2–MAPK kinase 2

p53R2:

p53-dependent RR small subunit

ROS:

reactive oxygen species

RR:

ribonucleotide reductase

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Acknowledgements

This research was supported by a Grant [M 1063901] [M 20706000032] from the Ministry of Science and Technology, the Korean Government and funds from the Chosun University, 2002.

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Author notes

  1. C Piao and M Jin: These authors contributed equally to this work.

Authors and Affiliations

  1. DNA Repair Research Center, Chosun University, Seosuk-dong, Gwangju, South Korea

    C Piao, M Jin, H B Kim, S M Lee, P N Amatya, I -Y Chang & H J You

  2. Department of Pharmacology, Chosun University, Seosuk-dong, Gwangju, South Korea

    C Piao, H B Kim & H J You

  3. Department of Biochemistry, School of Medicine, Yanbian University, Yanji, Jilin, China

    M Jin

  4. Department of Biochemistry, College of Medicine Cheju National University, Jeju, Jeju-do, South Korea

    J -W Hyun

  5. Department of Anatomy, Chosun University, Seosuk-dong, Gwangju, South Korea

    I -Y Chang

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Correspondence to H J You.

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Piao, C., Jin, M., Kim, H. et al. Ribonucleotide reductase small subunit p53R2 suppresses MEK–ERK activity by binding to ERK kinase 2. Oncogene 28, 2173–2184 (2009). https://doi.org/10.1038/onc.2009.84

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