Lymphangioleiomyomatosis — a wolf in sheep’s clothing

Henske, Elizabeth P.; McCormack, Francis X.

doi:10.1172/jci58709

Cited by 271 publications

(279 citation statements)

References 138 publications

(129 reference statements)

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“…Treatment of human patients with TSC with rapamycin or rapamycin analogs results in a decrease in the size of kidney and central nervous system tumors by 30-40%, with regrowth to the original size when the treatment is discontinued (Henske and McCormack 2012). Our data in fission yeast point to the possibility that strategies focused on Npr2-dependent regulation of mTOR activity could contribute to more complete and/or more durable therapeutic responses for patients with TSC and lymphangioleiomyomatosis, and for other tumors with mTORC1 activation, including many human malignancies.…”

Section: Tsc2 and Npr2 Play Different Roles In The Regulation Of Tor2mentioning

confidence: 99%

TORC1 Signaling Is Governed by Two Negative Regulators in Fission Yeast

Liu

Zhang

et al. 2013

Genetics

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The target of rapamycin (TOR) is a highly conserved protein kinase that regulates cell growth and metabolism. Here we performed a genome-wide screen to identify negative regulators of TOR complex 1 (TORC1) in Schizosaccharomyces pombe by isolating mutants that phenocopy Dtsc2, in which TORC1 signaling is known to be up-regulated. We discovered that Dnpr2 displayed similar phenotypes to Dtsc2 in terms of amino acid uptake defects and mislocalization of the Cat1 permease. However, Dnpr2 and Dtsc2 clearly showed different phenotypes in terms of rapamycin supersensitivity and Isp5 transcription upon various treatments. Furthermore, we showed that Tor2 controls amino acid homeostasis at the transcriptional and post-transcriptional levels. Our data reveal that both Npr2 and Tsc2 negatively regulate TORC1 signaling, and Npr2, but not Tsc2, may be involved in the feedback loop of a nutrient-sensing pathway.T HE target of rapamycin (TOR) plays vitally important roles in regulating cell growth and metabolism. TOR interacts with several proteins to form two structurally and functionally distinct complexes named TOR complex 1 (TORC1) and 2 (TORC2) Sabatini 2009, 2012). In response to environmental cues, TORC1 controls cell growth and differentiation by coordinating diverse cellular processes including transcription, translation, and autophagy. Research on TORC1 has generated a model of the complex TOR signaling network (Huang and Manning 2009;Orlova and Crino 2010;Laplante and Sabatini 2012). In the regulation of TORC1 signaling, four major signals have been identified, namely growth factors (insulin, IGF, etc.), energy status (AMP/ATP ratio), oxygen levels, and nutrients (amino acids) Sabatini 2009, 2012). In mammals, the tuberous sclerosis complex 1 and 2 (TSC1-TSC2) serves as a key point of signal integration. The growth factors stimulate TORC1 signaling via PI3K-Akt/ PKB-mediated phosphoinhibition of TSC2 (Inoki et al. 2002;Manning et al. 2002). The energy starvation inhibits TORC1 signaling via AMPK-dependent phosphoactivation of TSC2 (Inoki et al. 2003). Then, TSC2 negatively regulates TORC1 activity by converting GTP-bound Rheb (Ras homolog enriched in brain) into its inactive GDP-bound state (Inoki et al. 2003;Tee et al. 2003). The amino acids, in particular the branched-chain amino acid leucine, positively regulate TORC1. The TORC1 signaling remains sensitive to amino acid deprivation in TSC2 2/2 cells (Nobukuni et al. 2005), indicating that the activation of TORC1 by amino acids is independent of TSC2. Recently, it was demonstrated that TORC1 responds to amino acid availability via mechanisms involving Rag GTPases (Sancak et al. 2008). In the presence of amino acids, the Rag GTPases interact with TORC1, thereby promoting the translocation of TORC1 to the lysosomal membranes and facilitating Rheb's activation of TORC1 (Sancak et al. 2010).In budding yeast Saccharomyces cerevisiae, TOR1 and TOR2 genes were originally identified as the targets of rapamycin, and mutations in TOR1 or TOR2 genes confer resi...

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Section: Tsc2 and Npr2 Play Different Roles In The Regulation Of Tor2mentioning

confidence: 99%

TORC1 Signaling Is Governed by Two Negative Regulators in Fission Yeast

Liu

Zhang

et al. 2013

Genetics

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“…estrogen signaling | mTORC1 signaling | ERK signaling | EMT L ymphangioleiomyomatosis (LAM) is a destructive, progressive, multisystem disease in which smooth muscle-like "LAM cells" invade the lung (1)(2)(3)(4)(5)(6) and is associated with chylous pleural effusions, lymphatic obstruction, and renal angiomyolipomas (7). LAM occurs almost exclusively in women with onset often occurring in the childbearing years (5,6,8,9).…”

mentioning

confidence: 99%

“…LAM occurs almost exclusively in women with onset often occurring in the childbearing years (5,6,8,9). A hallmark of LAM is mutational inactivation of both alleles of the TSC2 gene, which encodes tuberin (TSC2) (1,2,4,5,10,11).…”

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confidence: 99%

Integration of mTOR and estrogen–ERK2 signaling in lymphangioleiomyomatosis pathogenesis

Ilter

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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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 (E 2 ) may play a role in the unique features of LAM. Using a LAM patient-derived cell line (bearing biallelic Tuberin inactivation), we demonstrate that E 2 stimulates a robust and biphasic activation of ERK2 and transcription of the late response-gene Fra1 associated with epithelialto-mesenchymal transition. In a carefully orchestrated collaboration, activated mTORC1/S6K1 signaling enhances the efficiency of Fra1 translation of Fra1 mRNA transcribed by the E 2 -ERK2 pathway, through the phosphorylation of the S6K1-dependent eukaryotic translation initiation factor 4B. Our results indicate that targeting the E 2 -ERK pathway in combination with the mTORC1 pathway may be an effective combination therapy for LAM.estrogen signaling | mTORC1 signaling | ERK signaling | EMT

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“…En ambas entidades se describen mutaciones en los genes TSC1 (Tuberous Sclerosis Complex 1), ubicado en el cromosoma 9q34 y TSC2 (Tuberous Sclerosis Complex 2) localizado en el cromosoma 16p13. Estos genes codifican para las proteínas hamartina y tuberina, encargadas de reducir el nivel de Rheb-GTP a través de la activación de una GTP-asa, con inhibición en el mTOR (mammalian target of rapamycin), un mediador de la proliferación y del crecimiento celular a través de la síntesis proteica (3)(4)(5).…”

Section: Fisiopatologíaunclassified

“…Estudios más recientes sugieren que la terapia con sirolimus y everolimus puede estabilizar la función pulmonar y reducir el volumen del quilotórax y los tamaños de los linfangioleiomiomas. Sin embargo, los pacientes presentan recaída al suspender el tratamiento (5,26,27).…”

Section: Pronóstico Y Tratamientounclassified

Linfangioleiomiomatosis esporádica. Presentación de un caso con enfermedad pulmonar y linfangioleiomiomas retroperitoneales

Gómez

Arroyave

et al. 2016

rev. colomb. neumol.

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La linfangioleiomiomatosis (LAM) es una enfermedad multisistémica asociada a mutaciones del gen TSC 2, que se presenta en forma esporádica (LMA-E) o asociada al complejo de esclerosis tuberosa (LAM-CET). La LAM cursa con enfermedad pulmonar relacionada con quistes en el parénquima. Sin embargo, los pacientes con LAM-E pueden evidenciar alteraciones mediastinales, retroperitoneales y renales, con adenomegalias, linfangioleiomiomas y angiomiolipomas.Presentamos el caso de una paciente con LAM-E y enfermedad pulmonar quística asociada a linfangioleiomiomas retroperitoneales y pélvicos.

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Lymphangioleiomyomatosis — a wolf in sheep’s clothing

Cited by 271 publications

References 138 publications

TORC1 Signaling Is Governed by Two Negative Regulators in Fission Yeast

TORC1 Signaling Is Governed by Two Negative Regulators in Fission Yeast

Integration of mTOR and estrogen–ERK2 signaling in lymphangioleiomyomatosis pathogenesis

Linfangioleiomiomatosis esporádica. Presentación de un caso con enfermedad pulmonar y linfangioleiomiomas retroperitoneales

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