This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Supplemental material
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Artero-Castro, A.
Right arrow Articles by Lleonart, M. E.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Artero-Castro, A.
Right arrow Articles by Lleonart, M. E.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, April 2009, p. 1855-1868, Vol. 29, No. 7
0270-7306/09/$08.00+0     doi:10.1128/MCB.01386-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Cold-Inducible RNA-Binding Protein Bypasses Replicative Senescence in Primary Cells through Extracellular Signal-Regulated Kinase 1 and 2 Activation{triangledown} ,{dagger}

Ana Artero-Castro,1 Francisco B. Callejas,1 Josep Castellvi,1 Hiroshi Kondoh,2 Amancio Carnero,3 Pablo J. Fernández-Marcos,3 Manuel Serrano,3 Santiago Ramón y Cajal,1 and Matilde E. Lleonart1*

Pathology Department, Fundació Institut de Recerca Hospital Vall d'Hebron, Passeig Vall d'Hebron 119-129, 08035 Barcelona, Spain,1 Department of Geriatric Medicine, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan,2 Spanish National Cancer Research Center, 3 Melchor Fernández Almagro Street, Madrid 28029, Spain3

Received 3 September 2008/ Returned for modification 19 September 2008/ Accepted 19 December 2008

Embryonic stem cells are immortalized cells whose proliferation rate is comparable to that of carcinogenic cells. To study the expression of embryonic stem cell genes in primary cells, genetic screening was performed by infecting mouse embryonic fibroblasts (MEFs) with a cDNA library from embryonic stem cells. Cold-inducible RNA-binding protein (CIRP) was identified due to its ability to bypass replicative senescence in primary cells. CIRP enhanced extracellular signal-regulated kinase 1 and 2 (ERK1/2) phosphorylation, and treatment with an MEK inhibitor decreased the proliferation caused by CIRP. In contrast to CIRP upregulation, CIRP downregulation decreased cell proliferation and resulted in inhibition of phosphorylated ERK1/2 inhibition. This is the first evidence that ERK1/2 activation, through the same mechanism as that described for a Val12 mutant K-ras to induce premature senescence, is able to bypass senescence in the absence of p16INK4a, p21WAF1, and p19ARF upregulation. Moreover, these results show that CIRP functions by stimulating general protein synthesis with the involvement of the S6 and 4E-BP1 proteins. The overall effect is an increase in kinase activity of the cyclin D1-CDK4 complex, which is in accordance with the proliferative capacity of CIRP MEFs. Interestingly, CIRP mRNA and protein were upregulated in a subgroup of cancer patients, a finding that may be of relevance for cancer research.

* Corresponding author. Mailing address: Fundació Institut de Recerca Hospital Vall d'Hebron, Passeig Vall d'Hebron 119-129, 08035 Barcelona, Spain. Phone: 34 93 4894169. Fax: 34 93 4894015. E-mail: melleona{at}ir.vhebron.net

{triangledown} Published ahead of print on 21 January 2009.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, April 2009, p. 1855-1868, Vol. 29, No. 7
0270-7306/09/$08.00+0     doi:10.1128/MCB.01386-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»