BTG proteins in cellular proliferation, differentiation, and mRNA turnover

• Applicant: Professor Dr. Georg Stoecklin
• Subject Area: General Genetics and Functional Genome Biology ; Biochemistry ; Cell Biology
• Term: from 2015 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 283844389

Control of mRNA decay is an important mechanism that contributes to the regulation of gene expression. In eukaryotes, removal of the poly-A tail of mRNAs constitutes a critical initiating step since deadenylated mRNAs are no longer translated and become, in somatic cells, targeted for degradation. Among the various enzymes catalyzing deadenylation, we and others showed that the exoribonuclease CAF1, a subunit of the CCR4-NOT complex, plays a major role in quantitative turnover of mRNAs. Moreover, recruitment of the CCR4-NOT complex to the 3-prime untranslated region of subsets of mRNAs, including targets of miRNAs, is a regulatory mechanism to destabilize specific mRNAs, and thus modulate gene expression. In metazoa, members of a group of small proteins collectively named BTG/Tob directly associate with CAF1. This led us to speculate that these proteins could play a role in mRNA decay. Indeed, we found that BTG2 expression stimulates the deadenylation of reporter mRNAs as well as endogenous transcripts. Similar observations were also made by others with Tob proteins. Besides their role in deadenylation, BTG/Tob proteins display antiproliferative properties as their ectopic expression in a variety of cell lines reduced cell proliferation. Moreover, their expression is frequently reduced in human cancers, and changes in BTG/Tob expression correlate with tumor grade and survival. However, the connection linking the biological and pathological characteristics of BTG/Tob factors to their molecular function in stimulating mRNA deadenylation remains unknown. The ultimate goal of our project is to address this question by elucidating the molecular mechanism by which BTG/Tob proteins control cell proliferation. We will focus our analysis mainly on the BTG2 protein, whose expression is induced rapidly and transiently by numerous stimuli. In the nervous system, the expression of BTG2 is regulated spatiotemporally during embryonic and adult neurogenesis. In mice, BTG2 overexpression during neurogenesis leads to microcephaly, while BTG2 deletion triggers impaired neuronal differentiation. BTG2 knockout (KO) mice also showed abnormalities in vertebral patterning, supporting a general role in embryonic development and cell differentiation. In this grant application, the two partners propose to join their interests and complementary expertise to 1) decipher the molecular mechanism by which BTG2 stimulates mRNA deadenylation; 2) explore the regulation of BTG2 and CAF1 through post-translational modifications; 3) investigate the mechanism by which BTG2 controls cellular proliferation; and 4) determine the role of BTG2 and mRNA turnover in cellular differentiation, in particular during neurogenesis. Beyond this proposal, our studies will set the basis for understanding how BTG/Tob proteins contribute to diseases.

• DFG Programme: Research Grants
• International Connection: France
• Partner Organisation: Agence Nationale de la Recherche / The French National Research Agency
• Cooperation Partner: Dr. Bertrand Séraphin