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  • The EMBO Journal (2004) 23, 406 - 417
  • doi:10.1038/sj.emboj.7600052

Published online: 15 January 2004

Competition of CUGBP1 and calreticulin for the regulation of p21 translation determines cell fate

Polina Iakova1, Guo-Li Wang1, Lubov Timchenko2, Marek Michalak3, Olivia M Pereira-Smith4, James R Smith4,5 and Nikolai A Timchenko1

  1. Department of Pathology and Huffington Center on Aging, Houston, TX, USA
  2. Department of Medicine, Baylor College of Medicine, One Baylor Plaza, Houston, TX, USA
  3. Department of Biochemistry, University of Alberta, Edmonoth, Alberta, Canada
  4. Department of Cellular and Structural Biology, San Antonio, TX, USA
  5. Department of Pathology, Sam and Ann Barshop Center for Longevity and Aging Studies, STCBM Building, San Antonio, TX, USA

Correspondence to:

Nikolai A Timchenko, Department of Pathology and Huffington Center on Aging, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA. Tel.: +1 713 798 1567; Fax: +1 713 798 4161; E-mail: nikolait@bcm.tmc.edu

Received 2 July 2003; Accepted 20 November 2003

Induction of p21 in senescent human fibroblasts plays a key role in the inactivation of cyclin-dependent kinases and the resulting irreversible growth arrest in the early stages of cell senescence. We found that RNA-binding proteins are critical regulators of p21 during senescence. Two RNA-binding proteins, CUGBP1 and calreticulin (CRT), interact with the same nucleotide sequences within the 5' region of p21 mRNA, but have opposite effects on the translation of p21 mRNA. CUGBP1 increases translation of p21 mRNA, whereas CRT blocks translation of p21 via stabilization of a stem–loop structure within the 5' region of the p21 mRNA. CUGBP1 and CRT compete for binding to p21 mRNA and thereby the regulation of p21 translation. In senescent fibroblasts, CUGBP1 displaces CRT from the p21 mRNA and releases CRT-dependent repression of p21 translation leading to growth arrest and development of a senescent phenotype. These data present evidence that competition between RNA-binding proteins for the regulation of p21 translation determines cell fate.

  • Keywords:

    • aging,
    • mRNA,
    • p21,
    • translation