BTG proteins in cellular proliferation, differentiation and mRNA turnover – BTG2mRNA

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 in this process as 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, and participates in decay pathways targeting specific mRNAs. Indeed, recruitment of the CCR4-NOT complex to the 3’ untranslated region of specific subsets of mRNAs by mRNA decay regulators, including miRNA-associated proteins, is a general mechanism to destabilize mRNA, and thus to modulate gene expression.

In metazoa, members of a group of small proteins collectively named BTG/Tob were shown to directly associate with CAF1. This led us to speculate that these proteins could play a role in mRNA decay. We confirmed this hypothesis by showing that BTG2 expression in cultured cells stimulates the deadenylation of reporters as well as of endogenous transcripts. Similar observations obtained by others with Tob proteins suggest that all BTG/Tob family members may stimulate deadenylation. 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. These changes in BTG/Tob expression have been correlated with tumor grade and survival. However, the mechanisms linking the biological and pathological characteristics of BTG/Tob factors to their molecular function in stimulating mRNA deadenylation are not yet clearly established. 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. Indeed, BTG2 is the smallest, and one of the best-studied members of the family. Its expression is induced rapidly and transiently by numerous stimuli and it has been implicated in several biological processes. BTG2 function during neurogenesis has been particularly examined as its expression is precisely 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 showed also abnormalities in vertebral patterning, supporting a general role in embryonic development and cell differentiation. Earlier, BTG2 was proposed to act as a transcriptional co-factor, yet our previous results suggest a major role in controlling the poly-A tail length of mRNAs. To strengthen this hypothesis, the two lab partners propose to join their interests and complementary expertise to decipher the molecular mechanism by which BTG2 stimulates mRNA deadenylation, including its regulation by post-translational modifications, and to link it to BTG2 impact on cell proliferation and cellular differentiation, in particular during neurogenesis. Beyond this proposal, our studies will set the basis for understanding how BTG/Tob proteins contribute to diseases.