The epithelial-mesenchymal transition (EMT), in which cells undergo a switch from a polarized, epithelial phenotype to a highly motile fibroblastic or mesenchymal phenotype is fundamental during embryonic development and can be reactivated in a variety of diseases including fibrosis and cancer. In addition to generating cells with increased migratory and invasive potential, recent data suggests that EMT represents a program that leads to the formation of both normal and neoplastic mammary epithelial stem cells, the latter representing cells that exhibit cancer stem cells (CSC)-like properties. Epithelial cells in the normal mammary gland, and by extension in other epithelial organs, employ components of the EMT program as the main route for entering into the stem cell (SC) state. We have identified a transcript-selective translational regulatory pathway in which a ribonucleoprotein (mRNP) complex, consisting of heterogeneous nuclear ribonucleoprotein E1 (hnRNP E1) and eukaryotic elongation factor 1A1 (eEF1A1), binds to a 3'-UTR regulatory BAT (TGF? activated translation) element and silences translation of mRNAs that mediate EMT. TGF? activates a kinase cascade terminating in the phosphorylation of hnRNP E1, by isoform-specific stimulation of protein kinase B?/Akt2, inducing the release of the mRNP complex from the 3'-UTR element, resulting in the reversal of translational silencing and increased expression of EMT-inducer mRNAs. Two of these mRNAs, the kinase Jak2 and a cytokine termed interleukin-like EMT-inducer (ILEI), and how they regulate TGF?-induced EMT and induction of mammary stem cells (MaSCs) are the focus of the current application. We hypothesize that the TGF?-induced EMT program mediates generation of MaSCs through hnRNP E1-regulated translational control of ILEI and Jak2. ILEI functions in an autocrine manner to mediate Jak2/Stat3-dependent and -independent signaling required for the EMT and generation of MaSCs. Thus, the goal of this proposal is to delineate the ILEI signaling pathway and to determine its functional significance in mediating MaSC formation.
The epithelial-mesenchymal transition (EMT) is a fundamental process during normal embryonic development but it can also be aberrantly re-activated in a variety of diseases including fibrosis and cancer. TGF? is one of the growth factors implicated in EMT. The successful pursuit of the studies proposed herein will elucidate the molecular mechanism through which TGF? mediates EMT and will provide insight into the design of strategies and therapeutics aimed at its prevention in pathological situations.
|Lv, Zongyang; Rickman, Kimberly A; Yuan, Lingmin et al. (2017) S. pombe Uba1-Ubc15 Structure Reveals a Novel Regulatory Mechanism of Ubiquitin E2 Activity. Mol Cell 65:699-714.e6|
|Janakiraman, H; House, R P; Talwar, S et al. (2017) Repression of caspase-3 and RNA-binding protein HuR cleavage by cyclooxygenase-2 promotes drug resistance in oral squamous cell carcinoma. Oncogene 36:3137-3148|
|Grelet, Simon; Link, Laura A; Howley, Breege et al. (2017) A regulated PNUTS mRNA to lncRNA splice switch mediates EMT and tumour progression. Nat Cell Biol 19:1105-1115|
|Howley, Breege V; Link, Laura A; Grelet, Simon et al. (2017) A CREB3-regulated ER-Golgi trafficking signature promotes metastatic progression in breast cancer. Oncogene :|
|Grelet, Simon; McShane, Ariel; Hok, Eveline et al. (2017) SPOt: A novel and streamlined microarray platform for observing cellular tRNA levels. PLoS One 12:e0177939|
|Noguchi, Ken; Dalton, Annamarie C; Howley, Breege V et al. (2017) Interleukin-like EMT inducer regulates partial phenotype switching in MITF-low melanoma cell lines. PLoS One 12:e0177830|
|Howley, B V; Hussey, G S; Link, L A et al. (2016) Translational regulation of inhibin ?A by TGF? via the RNA-binding protein hnRNP E1 enhances the invasiveness of epithelial-to-mesenchymal transitioned cells. Oncogene 35:1725-35|
|Link, Laura A; Howley, Breege V; Hussey, George S et al. (2016) PCBP1/HNRNP E1 Protects Chromosomal Integrity by Translational Regulation of CDC27. Mol Cancer Res 14:634-46|
|Brown, Andrew S; Mohanty, Bidyut K; Howe, Philip H (2015) Computational Identification of Post Translational Modification Regulated RNA Binding Protein Motifs. PLoS One 10:e0137696|
|Nasarre, Patrick; Gemmill, Robert M; Potiron, Vincent A et al. (2013) Neuropilin-2 Is upregulated in lung cancer cells during TGF-*1-induced epithelial-mesenchymal transition. Cancer Res 73:7111-21|
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