Mutational and Radiographic Analysis of Pulmonary  Disease Consistent with Lymphangioleiomyomatosis  and Micronodular Pneumocyte Hyperplasia in Women  with Tuberous Sclerosis

Franz, David Neal; Brody, Alan S.; Meyer, Cristopher A.; Leonard, Jennifer; Chuck, Gail; Dabora, Sandra L.; Sethuraman, Gopalan; Colby, Thomas V.; Kwiatkowski, David J.; McCormack, Francis X.

doi:10.1164/ajrccm.164.4.2011025

Cited by 258 publications

(172 citation statements)

References 39 publications

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“…Furthermore, unlike tuberous sclerosis, lymphangioleiomyomatosis has a gender bias, almost exclusively targeting women of childbearing age. Patients with lymphangioleiomyomatosis suffer from a progressive course of dyspnea, pneumothorax, and chylous pleural effusions (6). Exacerbations of lymphangioleiomyomatosis are often seen during pregnancy, and in some cases, the symptoms can be ameliorated with treatments that decrease endogenous estrogen levels, suggesting the involvement of steroid hormones in the pathogenesis of the disease.…”

Section: Introductionmentioning

confidence: 99%

Tuberin Nuclear Localization Can Be Regulated by Phosphorylation of Its Carboxyl Terminus

York

Lou

2006

Molecular Cancer Research

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Tuberin, the tuberous sclerosis 2 (TSC2) gene product, has been identified as a tumor suppressor protein genetically implicated in the pathology of tuberous sclerosis and the female-specific lung disease lymphangioleiomyomatosis. Tuberin and its predominant cytoplasmic binding partner hamartin have been shown to complex with a variety of intracellular signaling regulators and affect the processes of protein translation, cellular proliferation, cellular migration, and cellular transcription. In previous studies, we have presented evidence for tuberin binding to the calcium-dependent intracellular signaling protein calmodulin (CaM), overlap of tuberin CaM binding domain with a binding domain for estrogen receptor A, and the phosphorylation-associated nuclear localization of tuberin. In the study presented here, we expand our findings on the mechanism of tuberin nuclear localization to show that the CaM-estrogen receptor-A binding domain of tuberin can also serve as a tuberin nuclear localization sequence. Furthermore, we identify an Akt/p90 ribosomal S6 kinase-1 phosphorylation site within the carboxyl terminus of tuberin that can regulate tuberin nuclear localization and significantly affect the ability of tuberin to modulate estrogen genomic signaling events. These findings suggest a link between tuberin nuclear localization and a variety of intracellular signaling events that have direct implications with respect to the role of tuberin in the pathology of tuberous sclerosis and lymphangioleiomyomatosis. (Mol Cancer Res 2006;4(11):885 -97)

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Section: Introductionmentioning

confidence: 99%

Tuberin Nuclear Localization Can Be Regulated by Phosphorylation of Its Carboxyl Terminus

York

Lou

2006

Molecular Cancer Research

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“…2 Lymphangioleiomyomatosis, the major pulmonary manifestation in women with the tuberous sclerosis complex, is a progressive lung disease characterized by infiltration of smooth-muscle cells and formation of parenchymal cysts. 3 Sporadic lymphangioleiomyomatosis can develop in women without the tuberous sclerosis complex, owing to somatic mutations in tuberous sclerosis genes. 4 The cells comprising the lymphangioleiomyomatosis lesions and angiomyolipomas appear to arise from a common source.…”

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Sirolimus for Angiomyolipoma in Tuberous Sclerosis Complex or Lymphangioleiomyomatosis

et al. 2008

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“…LAM affects 30Ϫ40% of women with TSC (2,3). In a Mayo Clinic series, LAM was the third most frequent cause of TSC-related death, after renal disease and brain tumors (4).…”

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Estrogen promotes the survival and pulmonary metastasis of tuberin-null cells

Robb

Morrison

et al. 2009

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

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Lymphangioleiomyomatosis (LAM) is an often fatal disease primarily affecting young women in which tuberin (TSC2)-null cells metastasize to the lungs. The mechanisms underlying the striking female predominance of LAM are unknown. We report here that 17-␤-estradiol (E2) causes a 3-to 5-fold increase in pulmonary metastases in male and female mice, respectively, and a striking increase in circulating tumor cells in mice bearing tuberin-null xenograft tumors. E 2-induced metastasis is associated with activation of p42/44 MAPK and is completely inhibited by treatment with the MEK1/2 inhibitor, CI-1040. In vitro, E 2 inhibits anoikis of tuberin-null cells. Finally, using a bioluminescence approach, we found that E 2 enhances the survival and lung colonization of intravenously injected tuberin-null cells by 3-fold, which is blocked by treatment with CI-1040. Taken together these results reveal a new model for LAM pathogenesis in which activation of MEKdependent pathways by E 2 leads to pulmonary metastasis via enhanced survival of detached tuberin-null cells.L AM, the pulmonary manifestation of tuberous sclerosis complex (TSC), affects women almost exclusively (1). LAM affects 30Ϫ40% of women with TSC (2, 3). In a Mayo Clinic series, LAM was the third most frequent cause of TSC-related death, after renal disease and brain tumors (4). LAM can also occur in women who do not have germline mutations in TSC1 or TSC2 (sporadic LAM). LAM cells from both TSC-LAM and sporadic LAM carry inactivating mutations in both alleles of the TSC1 or TSC2 genes (5). The protein products of TSC1 and TSC2, hamartin and tuberin, respectively, form heterodimers (6, 7) that inhibit the small GTPase Ras homologue enriched in brain (Rheb), via tuberin's highly conserved GTPase activating domain. In its active form, Rheb activates the mammalian target of rapamycin (mTOR) complex 1 (TORC1), which is a key regulator of protein translation, cell size, and cell proliferation (8). Evidence of TORC1 activation, including hyperphosphorylation of ribosomal protein S6, has been observed in tumor specimens from TSC patients and LAM patients (9-11). Independent of its activation of mTOR, Rheb inhibits the activity of B-Raf and C-Raf/Raf-1 kinase, resulting in reduced phosphorylation of p42/44 MAPK (12-14), but the impact of the Raf/MEK/ MAPK pathway on disease pathogenesis is undefined.LAM is characterized pathologically by widespread proliferation of abnormal smooth muscle cells and by cystic changes within the lung parenchyma (1). About 60% of women with the sporadic form of LAM also have renal angiomyolipomas. The presence of TSC2 mutations in LAM cells and renal angiomyolipoma cells from women with sporadic LAM, but not in normal tissues, has led to the hypothesis that LAM cells spread to the lungs via a metastatic mechanism, despite the fact that LAM cells have a histologically benign appearance (15,16). Genetic and fluorescent in situ hybridization analyses of recurrent LAM after lung transplantation support this benign metastatic model (16).The female...

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Mutational and Radiographic Analysis of Pulmonary Disease Consistent with Lymphangioleiomyomatosis and Micronodular Pneumocyte Hyperplasia in Women with Tuberous Sclerosis

Cited by 258 publications

References 39 publications

Tuberin Nuclear Localization Can Be Regulated by Phosphorylation of Its Carboxyl Terminus

Tuberin Nuclear Localization Can Be Regulated by Phosphorylation of Its Carboxyl Terminus

Sirolimus for Angiomyolipoma in Tuberous Sclerosis Complex or Lymphangioleiomyomatosis

Estrogen promotes the survival and pulmonary metastasis of tuberin-null cells

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