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Molecular and Cellular Biology, August 2009, p. 4341-4351, Vol. 29, No. 16
0270-7306/09/$08.00+0     doi:10.1128/MCB.00210-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

p38 Mitogen-Activated Protein Kinase- and HuR-Dependent Stabilization of p21Cip1 mRNA Mediates the G1/S Checkpoint{triangledown}

Vanesa Lafarga,1 Ana Cuadrado,1* Isabel Lopez de Silanes,1 Rocio Bengoechea,2 Oscar Fernandez-Capetillo,1 and Angel R. Nebreda1*

CNIO (Spanish National Cancer Center), Melchor Fernandez Almagro 3, 28029 Madrid, Spain,1 Departamento de Anatomia y Biologia Celular, Universidad de Cantabria, Santander, Spain2

Received 16 February 2009/ Returned for modification 12 March 2009/ Accepted 17 May 2009

Activation of p38 mitogen-activated protein kinase (MAPK) plays an important role in the G2/M cell cycle arrest induced by DNA damage, but little is known about the role of this signaling pathway in the G1/S transition. Upregulation of the cyclin-dependent kinase inhibitor p21Cip1 is thought to make a major contribution to the G1/S cell cycle arrest induced by {gamma} radiation. We show here that inhibition of p38 MAPK impairs p21Cip1 accumulation and, as a result, the ability of cells to arrest in G1 in response to {gamma} radiation. We found that p38 MAPK induces p21Cip1 mRNA stabilization, without affecting its transcription or the stability of the protein. In particular, p38 MAPK phosphorylates the mRNA binding protein HuR on Thr118, which results in cytoplasmic accumulation of HuR and its enhanced binding to the p21Cip1 mRNA. Our findings help to understand the emerging role of p38 MAPK in the cellular responses to DNA damage and reveal the existence of p53-independent networks that cooperate in modulating p21Cip1 levels at the G1/S checkpoint.

* Corresponding author. Mailing address: CNIO (Spanish National Cancer Center), Melchor Fernandez Almagro 3, 28029 Madrid, Spain. Phone: 34-917328000. Fax: 34-917328033. E-mail for Ana Cuadrado: acuadrado{at}cnio.es. E-mail for Angel R. Nebreda: anebreda{at}cnio.es

{triangledown} Published ahead of print on 15 June 2009.

Molecular and Cellular Biology, August 2009, p. 4341-4351, Vol. 29, No. 16
0270-7306/09/$08.00+0     doi:10.1128/MCB.00210-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Cuadrado, M., Gutierrez-Martinez, P., Swat, A., Nebreda, A. R., Fernandez-Capetillo, O. (2009). p27Kip1 Stabilization Is Essential for the Maintenance of Cell Cycle Arrest in Response to DNA Damage. Cancer Res. 69: 8726-8732 [Abstract] [Full Text]  


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