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Molecular and Cellular Biology, June 2007, p. 3936-3950, Vol. 27, No. 11
0270-7306/07/$08.00+0     doi:10.1128/MCB.01776-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Ubiquitin-Independent Proteasomal Degradation of Fra-1 Is Antagonized by Erk1/2 Pathway-Mediated Phosphorylation of a Unique C-Terminal Destabilizer{triangledown}

Jihane Basbous,1 Dany Chalbos,2,3 Robert Hipskind,1 Isabelle Jariel-Encontre,1 and Marc Piechaczyk1*

Institut de Génétique Moléculaire de Montpellier, CNRS, 1919 Route de Mende, Montpellier F-34293, France,1 INSERM U540, Montpellier F-34090, France,2 University Montpellier I, Montpellier F-34000, France3

Received 20 September 2006/ Returned for modification 12 November 2006/ Accepted 10 March 2007

Fra-1, a transcription factor that is phylogenetically and functionally related to the proto-oncoprotein c-Fos, controls many essential cell functions. It is expressed in many cell types, albeit with differing kinetics and abundances. In cells reentering the cell cycle, Fra-1 expression is transiently stimulated albeit later than that of c-Fos and for a longer time. Moreover, Fra-1 overexpression is found in cancer cells displaying high Erk1/2 activity and has been linked to tumorigenesis. One crucial point of regulation of Fra-1 levels is controlled protein degradation, the mechanism of which remains poorly characterized. Here, we have combined genetic, pharmacological, and signaling studies to investigate this process in nontransformed cells and to elucidate how it is altered in cancer cells. We report that the intrinsic instability of Fra-1 depends on a single destabilizer contained within the C-terminal 30 to 40 amino acids. Two serines therein, S252 and S265, are phosphorylated by kinases of the Erk1/2 pathway, which compromises protein destruction upon both normal physiological induction and tumorigenic constitutive activation of this cascade. Our data also indicate that Fra-1, like c-Fos, belongs to a small group of proteins that may, under certain circumstances, undergo ubiquitin-independent degradation by the proteasome. Our work reveals both similitudes and differences between Fra-1 and c-Fos degradation mechanisms. In particular, the presence of a single destabilizer within Fra-1, instead of two that are differentially regulated in c-Fos, explains the much faster turnover of the latter when cells traverse the G0/G1-to-S-phase transition. Finally, our study offers further insights into the signaling-regulated expression of the other Fos family proteins.

* Corresponding author. Mailing address: Institut de Génétique Moléculaire de Montpellier, CNRS, 1919 Route de Mende, Montpellier F-34293, France. Phone: (33) 4 67 61 36 71. Fax: (33) 4 67 04 02 31. E-mail: marc.piechaczyk{at}igmm.cnrs.fr

{triangledown} Published ahead of print on 19 March 2007.

Molecular and Cellular Biology, June 2007, p. 3936-3950, Vol. 27, No. 11
0270-7306/07/$08.00+0     doi:10.1128/MCB.01776-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Farras, R., Baldin, V., Gallach, S., Acquaviva, C., Bossis, G., Jariel-Encontre, I., Piechaczyk, M. (2008). JunB Breakdown in Mid-/Late G2 Is Required for Down-Regulation of Cyclin A2 Levels and Proper Mitosis. Mol. Cell. Biol. 28: 4173-4187 [Abstract] [Full Text]  
  • Malnou, C. E., Salem, T., Brockly, F., Wodrich, H., Piechaczyk, M., Jariel-Encontre, I. (2007). Heterodimerization with Jun Family Members Regulates c-Fos Nucleocytoplasmic Traffic. J. Biol. Chem. 282: 31046-31059 [Abstract] [Full Text]  


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