title: Integration of mTOR and estrogen-ERK2 signaling in lymphangioleiomyomatosis pathogenesis.
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.
authors: Department of Cell Biology, Harvard Medical School, Boston, MA, 02115.
authors: Xiaoxiao
authors: X
authors: Gu
authors: Jane J
authors: JJ
authors: Yu
authors: Didem
authors: D
authors: Ilter
authors: Nickolas
authors: N
authors: Blenis
authors: Elizabeth Petri
authors: EP
authors: Henske
authors: John
authors: J
authors: Blenis
mesh_terms: D029681:Arabidopsis Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement; D058750:Epithelial-Mesenchymal Transition; D004958:Estradiol / Q000378:metabolism*; D039642:Eukaryotic Initiation Factors / Q000378:metabolism; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D018192:Lymphangioleiomyomatosis / Q000209:etiology* / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D000076222:Mechanistic Target of Rapamycin Complex 1; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism; D009361:Neoplasm Invasiveness; D011247:Pregnancy; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D029681:Arabidopsis Proteins; D039642:Eukaryotic Initiation Factors; C472140:FRA1 protein, Arabidopsis; D008869:Microtubule-Associated Proteins; D046912:Multiprotein Complexes; D012333:RNA, Messenger; D012334:RNA, Neoplasm; C031799:eIF-4B; D004958:Estradiol; C546842:MTOR protein, human; D000076222:Mechanistic Target of Rapamycin Complex 1; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; C448901:ribosomal protein S6 kinase, 70kD, polypeptide 1; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D020123:Sirolimus
keywords: EMT; ERK signaling; estrogen signaling; mTORC1 signaling
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