Abstract
Lymphangioleiomyomatosis (LAM) is a destructive lung disease of women associated with the metastasis of tuberin-null cells with hyperactive mammalian target of rapamycin complex 1 (mTORC1) activity. Clinical trials with the mTORC1 inhibitor rapamycin have revealed partial efficacy but are not curative. Pregnancy appears to exacerbate LAM, suggesting that estrogen (E2) may play a role in the unique features of LAM. Using a LAM patient-derived cell line (bearing biallelic Tuberin inactivation), we demonstrate that E2 stimulates a robust and biphasic activation of ERK2 and transcription of the late response-gene Fra1 associated with epithelial-to-mesenchymal transition. In a carefully orchestrated collaboration, activated mTORC1/S6K1 signaling enhances the efficiency of Fra1 translation of Fra1 mRNA transcribed by the E2-ERK2 pathway, through the phosphorylation of the S6K1-dependent eukaryotic translation initiation factor 4B. Our results indicate that targeting the E2-ERK pathway in combination with the mTORC1 pathway may be an effective combination therapy for LAM.
Keywords:
EMT; ERK signaling; estrogen signaling; mTORC1 signaling.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Arabidopsis Proteins / genetics
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Arabidopsis Proteins / metabolism
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Cell Line, Tumor
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Cell Movement
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Epithelial-Mesenchymal Transition
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Estradiol / metabolism*
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Eukaryotic Initiation Factors / metabolism
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Female
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Gene Knockdown Techniques
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Humans
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Lymphangioleiomyomatosis / etiology*
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Lymphangioleiomyomatosis / genetics
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Lymphangioleiomyomatosis / metabolism*
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MAP Kinase Signaling System
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Mechanistic Target of Rapamycin Complex 1
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Microtubule-Associated Proteins / genetics
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Microtubule-Associated Proteins / metabolism
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Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors
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Mitogen-Activated Protein Kinase 1 / genetics
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Mitogen-Activated Protein Kinase 1 / metabolism*
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Multiprotein Complexes / antagonists & inhibitors
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Multiprotein Complexes / metabolism
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Neoplasm Invasiveness
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Pregnancy
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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RNA, Neoplasm / genetics
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RNA, Neoplasm / metabolism
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Ribosomal Protein S6 Kinases, 70-kDa / metabolism
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Signal Transduction / drug effects
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Sirolimus / pharmacology
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TOR Serine-Threonine Kinases / antagonists & inhibitors
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TOR Serine-Threonine Kinases / metabolism*
Substances
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Arabidopsis Proteins
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Eukaryotic Initiation Factors
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FRA1 protein, Arabidopsis
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Microtubule-Associated Proteins
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Multiprotein Complexes
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RNA, Messenger
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RNA, Neoplasm
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eIF-4B
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Estradiol
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MTOR protein, human
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Mechanistic Target of Rapamycin Complex 1
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Ribosomal Protein S6 Kinases, 70-kDa
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TOR Serine-Threonine Kinases
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ribosomal protein S6 kinase, 70kD, polypeptide 1
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MAPK1 protein, human
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Mitogen-Activated Protein Kinase 1
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Sirolimus