Comprehensive detection of human terminal oligo-pyrimidine (TOP) genes and analysis of their characteristics

Abstract

Although the knowledge accumulated on the transcriptional regulations of eukaryotes is significant, the knowledge on their translational regulations remains limited. Thus, we performed a comprehensive detection of terminal oligo-pyrimidine (TOP), which is one of the well-characterized cis-regulatory motifs for translational controls located immediately downstream of the transcriptional start sites of mRNAs. Utilizing our precise 5′-end information of the full-length cDNAs, we could screen 1645 candidate TOP genes by position specific matrix search. Among them, not only 75 out of 78 ribosomal protein genes but also eight previously identified non-ribosomal-protein TOP genes were included. We further experimentally validated the translational activities of 83 TOP candidate genes. Clear translational regulations exerted on the stimulation of 12-O-tetradecanoyl-1-phorbol-13-acetate for at least 41 of them was observed, indicating that there should be a few hundreds of human genes which are subjected to regulation at translation levels via TOPs. Our result suggests that TOP genes code not only formerly characterized ribosomal proteins and translation-related proteins but also a wider variety of proteins, such as lysosome-related proteins and metabolism-related proteins, playing pivotal roles in gene expression controls in the majority of cellular mRNAs.

The Translational Controlled Tumour Protein TCTP: Biological Functions and Regulation

“…for the human, mouse and rabbit mRNAs (Thiele et al 1998(Thiele et al , 2000Fiucci et al 2003). The 5 0 -TOP motif is a hallmark for a specific group of mRNAs that are under translational control through the mTOR complex 1 (mTORC1) signalling pathway (Meyuhas and Kahan 2015;Yamashita et al 2008). We have recently demonstrated that growth induction of TCTP expression is indeed regulated through this pathway (Bommer et al 2015).…”

“…This group of mRNAs largely comprises those mRNAs coding for components of the translational apparatus, in particular ribosomal proteins and translation factors (Meyuhas and Kahan 2015;Meyuhas 2000). The observations that the mRNA of TCTP also bears a 5 0 -TOP (Yamashita et al 2008;Meyuhas 2000) and is regulated through the mTORC1 pathway (Bommer et al 2015) would suggest that TCTP also participates in the activities (or regulation) of the translational machinery. In fact, as early as 2003, the Telerman group identified translation elongation factor eEF1A and its guanine nucleotide exchange factor eEF1Bβ as TCTP-interacting partners (Cans et al 2003).…”

“…The main representatives of this group of mRNAs are those which encode components of the translational apparatus (Meyuhas and Kahan 2015). Since the TCTP mRNA also features a 5 0 -TOP (Yamashita et al 2008), we recently revisited this topic and showed that the growth factor-dependent induction of TCTP synthesis is indeed regulated through the PI3K/Akt/mTORC1 pathway and eIF4E (Bommer et al 2015). We also found that treatment of colon cancer cells with DNA-damaging anticancer drugs leads to a four-fold up-regulation of TCTP levels through the mTORC1 pathway (Bommer et al 2017).…”

Growth-factor dependent expression of the translationally controlled tumour protein TCTP is regulated through the PI3-K/Akt/mTORC1 signalling pathway

“…Translation of a particular subset of mRNAs, called TOP-mRNAs (based on the presence of a 5'-tract of oligopyrimidines, 5'-TOP), is specifically up-regulated upon mTORC1 activation, although the exact mechanism for this still remains to be elucidated [41,42]. The mRNAs for ribosomal proteins and translation factors [43][44][45] are the classical representatives of this group, but recently also mRNAs for other proteins where shown to bear this signature [45]. The mRNA coding for TCTP also contains a 5'-TOP [14,30,46]; in fact several potential TOP sequences were identified in the vicinity of its transcription start site [45].…”

“…The mRNAs for ribosomal proteins and translation factors [43][44][45] are the classical representatives of this group, but recently also mRNAs for other proteins where shown to bear this signature [45]. The mRNA coding for TCTP also contains a 5'-TOP [14,30,46]; in fact several potential TOP sequences were identified in the vicinity of its transcription start site [45]. Therefore, we hypothesised that its translation is specifically A C C E P T E D M A N U S C R I P T …”