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  • The EMBO Journal (2003) 22, 5582 - 5592
  • doi:10.1093/emboj/cdg515

Upstream AUGs in embryonic proinsulin mRNA control its low translation level

Catalina Hernández-Sánchez1, Alicia Mansilla1, Enrique J. de la Rosa1, G.Elisabeth Pollerberg2, Encarna Martínez-Salas3 and Flora de Pablo1

  1. Group of Growth Factors in Vertebrate Development, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Ramiro de Maeztu 9, E-28040 Madrid, Spain
  2. Department of Developmental Neurobiology, Institute of Zoology, University of Heidelberg, Im Neuenheimer Feld 232, D-69120 Heidelberg, Germany
  3. Centro de Biología Molecular 'Severo Ochoa', Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Cantoblanco, E-28049 Madrid, Spain

Correspondence to:

Catalina Hernández-Sánchez, E-mail: chernandez@cib.csic.es

Received 26 March 2003; Accepted 15 August 2003; Revised 11 August 2003

Proinsulin is expressed prior to development of the pancreas and promotes cell survival. Here we study the mechanism affecting the translation efficiency of a specific embryonic proinsulin mRNA. This transcript shares the coding region with the pancreatic form, but presents a 32 nt extended leader region. Translation of proinsulin is markedly reduced by the presence of two upstream AUGs within the 5' extension of the embryonic mRNA. This attenuation is lost when the two upstream AUGs are mutated to AAG, leading to translational efficiency similar to that of the pancreatic mRNA. The upstream AUGs are recognized as initiator codons, because expression of upstream ORF is detectable from the embryonic transcript, but not from the mutated or the pancreatic mRNAs. Strict regulation of proinsulin biosynthesis appears to be necessary, since exogenous proinsulin added to embryos in ovo decreased apoptosis and generated abnormal developmental traits. A novel mechanism for low level proinsulin expression thus relies on upstream AUGs within a specific form of embryonic proinsulin mRNA, emphasizing its importance as a tightly regulated developmental signal.

  • Keywords:

    • developmental cell death,
    • proinsulin translation,
    • upAUGs