The race to decipher the top secrets of TOP mRNAs

• TOP mRNAs encode proteins of the translational machinery.
• The hallmark of TOP mRNAs is a 5′ terminal oligopyrimidine (5′ TOP) motif.
• TOP mRNAs are translationally repressed when subjected to a variety of stresses.
• Translational control of TOP mRNAs is mediated by the mTOR pathway
• The identity of the translational trans-acting factor of TOP mRNAs is still elusive

Cells encountering hostile growth conditions, like those residing in the middle of a newly developing solid tumor, conserve resources and energy by downregulating protein synthesis. One mechanism in this response is the translational repression of multiple mRNAs that encode components of the translational apparatus. This coordinated translational control is carried through a common cis-regulatory element, the 5′ Terminal OligoPyrimidine motif (5′TOP), after which these mRNAs are referred to as TOP mRNAs. Subsequent to the initial structural and functional characterization of members of this family, the research of TOP mRNAs has progressed in three major directions: a) delineating the landscape of the family; b) establishing the pathways that transduce stress cues into selective translational repression; and c) attempting to decipher the most proximal trans-acting factor(s) and defining its mode of action — a repressor or activator. The present chapter critically reviews the development in these three avenues of research with a special emphasis on the two “top secrets” of the TOP mRNA family: the scope of its members and the identity of the proximal cellular regulator(s). This article is part of a Special Issue entitled: Translation and Cancer.