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. EMT is associated with changes in cell-cell adhesion, remodeling of extracellular matrix, and enhanced migratory activity, all properties that enable tumor cells to metastasize. Numerous cytokines and autocrine growth factors, including TGF?, have been implicated in EMT. Despite intensive transcriptional array analysis of human tumors, the identity and validation of 'EMT signature genes'remains elusive. We have elucidated a novel, post-transcriptional pathway by which TGF? modulates expression of EMT-inducer proteins and EMT itself. We identified that heterogeneous nuclear ribonucleoprotein E1 (hnRNP E1) binds to a structural, 33-nucleotide TGFbeta-activated translation (BAT) element in the 3'-UTR of two bona fide EMT-inducer transcripts, disabled-2 (Dab2) and interleukin-like EMT inducer (ILEI), thereby repressing their translation in NMuMG and EpRas cells, two established in vitro models of EMT. In this pathway, TGF? activates a kinase cascade terminating in phosphorylation of Ser43 of hnRNP E1 by isoform-specific stimulation of protein kinase B?/Akt2, inducing its release from the BAT element and causing translational activation of Dab2 and ILEI mRNAs. Modulation of hnRNP E1 expression, or its post-translational modification, alters not only TGF?-mediated translational activation of the target transcripts, but also EMT. Recently, we have purified the ribonucleoprotein (mRNP) complex binding to the BAT element and have identified elongation factor 1A1 (EF1A1) as a second, functional component of this translational silencing pathway. We hypothesize that translational regulation of Dab2 and ILEI, as well as other EMT-inducer transcripts, constitutes a TGF?-inducible post-transcriptional regulon mediated by hnRNP E1 and EF1A1, which functionally regulates EMT during tumorigenesis. The goal of this proposal is to use this mRNP complex as a model target of TGF? signaling, to delineate its regulation of protein synthesis in response to TGF? and to determine its functional significance in mediating tumorigenesis and metastatic progression.
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.
|Emetu, Sophia; Troiano, Morgan; Goldmintz, Jacob et al. (2018) Metabolic Labeling and Profiling of Transfer RNAs Using Macroarrays. J Vis Exp :|
|Noguchi, Ken; Dincman, Toros A; Dalton, Annamarie C et al. (2018) Interleukin-like EMT inducer (ILEI) promotes melanoma invasiveness and is transcriptionally up-regulated by upstream stimulatory factor-1 (USF-1). J Biol Chem 293:11401-11414|
|Howley, Breege V; Howe, Philip H (2018) TGF-beta signaling in cancer: post-transcriptional regulation of EMT via hnRNP E1. Cytokine :|
|Howley, Breege V; Link, Laura A; Grelet, Simon et al. (2018) A CREB3-regulated ER-Golgi trafficking signature promotes metastatic progression in breast cancer. Oncogene 37:1308-1325|
|Howley, Breege V; Howe, Philip H (2018) Metastasis-associated upregulation of ER-Golgi trafficking kinetics: regulation of cancer progression via the Golgi apparatus. Oncoscience 5:142-143|
|Grelet, Simon; Geslain, Renaud; Howe, Philip H (2018) EMT does not work regular shifts. Cell Cycle 17:141-142|
|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|
|Gencer, Salih; Oleinik, Natalia; Kim, Jisun et al. (2017) TGF-? receptor I/II trafficking and signaling at primary cilia are inhibited by ceramide to attenuate cell migration and tumor metastasis. Sci Signal 10:|
|Qie, Shuo; Majumder, Mrinmoyee; Mackiewicz, Katarzyna et al. (2017) Fbxo4-mediated degradation of Fxr1 suppresses tumorigenesis in head and neck squamous cell carcinoma. Nat Commun 8:1534|
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