Featured Research Project
Regulation of Transcript-Selective Translation by TGFβ: Deciphering the control of the TGFβ pathway is key to understanding the initiation, growth, and metastasis of multiple tumor types, including colon, prostate, and breast cancer. Using breast cancer models, Dr. Philip H. Howe’s laboratory has delineated a novel post-transcriptional regulatory pathway by which TGFβ modulates expression of epithelial-mesenchymal transition (EMT)-inducer proteins and EMT itself. Specifically, heterogeneous ribonucleoprotein E1 (hnRNP E1) and elongation factor 1A1 (EF1A1) form a mRNP complex that binds to a structural, TGFβ-activated translation (BAT) element in the 3’-UTR of EMT inducer transcripts and represses their translation.
TGF-β activates PI3K and, subsequently, AKT2, via its non-canonical signaling pathway. AKT2 then phosphorylates an RNA-binding protein, hnRNP E1 at serine 43. Importantly, this phosphorylation causes the release of hnRNP E1 (E1) from the 3’UTR BAT structure of mRNAs and allows for translational elongation to proceed and ultimately EMT to occur as shown in the figure. This seminal observation suggests the possibility that inhibitors of the AKT kinase could block this pathway and AKT inhibitors could reverse the EMT necessary to induce metastasis.
Using hnRNP E1 as a target, Dr. Howe has made an additional important observation that translational regulation of EMT/metastatic mRNA transcripts during metastasis mimics how transcript-selective translational control regulates early embryonic mRNAs, a stage when cell proliferation and migration are most active. Based on these observations, the Howe laboratory demonstrates that attenuation of hnRNP E1 expression in non-invasive mammary gland epithelial cells induced EMT, allowed these cells to effectively grow in mammosphere culture, and enabled cells to form metastatic lesions in vivo. This induced EMT in normal mammary gland epithelial cells was able to reconstitute a differentiated mammary gland following implantation into cleared fat pads. These results provide evidence for the importance of this mechanism in facilitating the reprogramming of epithelial cells and promoting their ability to self-renew, like stem cells, a key property of cancer cells.