title: Cold-inducible RNA-binding protein bypasses replicative senescence in primary cells through extracellular signal-regulated kinase 1 and 2 activation.
abstract: 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 p16(INK4a), p21(WAF1), and p19(ARF) 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.
authors.affiliation: Pathology Department, Fundació Institut de Recerca Hospital Vall d'Hebron, Passeig Vall d'Hebron 119-129, 08035 Barcelona, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Artero-Castro
authors.forename: Francisco B
authors.initials: FB
authors.lastname: Callejas
authors.forename: Josep
authors.initials: J
authors.lastname: Castellvi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kondoh
authors.forename: Amancio
authors.initials: A
authors.lastname: Carnero
authors.forename: Pablo J
authors.initials: PJ
authors.lastname: Fernández-Marcos
authors.forename: Manuel
authors.initials: M
authors.lastname: Serrano
authors.forename: Santiago
authors.initials: S
authors.lastname: Ramón y Cajal
authors.forename: Matilde E
authors.initials: ME
authors.lastname: Lleonart
mesh_terms: D000818:Animals; D002461:Cell Line, Transformed; D049109:Cell Proliferation; D016922:Cellular Senescence; D015536:Down-Regulation / Q000235:genetics; D004622:Embryo, Mammalian / Q000166:cytology / Q000201:enzymology; D004789:Enzyme Activation; D005347:Fibroblasts / Q000166:cytology / Q000201:enzymology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D009369:Neoplasms / Q000201:enzymology / Q000235:genetics; D010766:Phosphorylation; D014176:Protein Biosynthesis; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C491390:CIRBP protein, human; C106176:Cirbp protein, mouse; D016601:RNA-Binding Proteins; D019950:Mitogen-Activated Protein Kinase 1