Estrogen-induced Smooth Muscle Cell Growth Is Regulated by Tuberin and Associated with Altered Activation of Platelet-derived Growth Factor Receptor-β and ERK-1/2

Finlay, Geraldine A.; York, Brian; Karas, Richard H.; Fanburg, Barry L.; Zhang, Hongbing; Kwiatkowski, David J.; Noonan, Daniel J.

doi:10.1074/jbc.m401912200

Cited by 70 publications

(59 citation statements)

References 56 publications

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“…This pathway is inhibited in cells lacking TSC2 via Rheb's inhibition of B-Raf and C-Raf/Raf-1 kinase (13,14). E 2 has been shown to activate p42/44 MAPK in ELT3 cells and in LAM patient-derived cells (11,20,21). To confirm that E 2 activates MAPK in ELT3 cells, we treated the cells with 10 nM E 2 and examined the phosphorylation status of p42/44 MAPK by immunoblotting.…”

Section: Estrogen Activates P42/44 Mapk In Elt3 Cells In Vitro and Inmentioning

confidence: 99%

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

Robb

Morrison

et al. 2009

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

157

198

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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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Section: Estrogen Activates P42/44 Mapk In Elt3 Cells In Vitro and Inmentioning

confidence: 99%

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

Robb

Morrison

et al. 2009

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

157

198

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“…Moreover, the normal feedback mechanisms that limit cell proliferation can be blocked by rapamycin. Finally, TSC2 and Rheb participate in signaling mechanisms other than the mTOR pathway that contribute to the cytoskeletal, 132 hormonal, 137 and proliferative 142 characteristics of neoplastic cells. Further characterization of the mTOR complexes and their signal integration functions will lead to therapeutic approaches for LAM and neoplasia that simultaneously target multiple receptors and signaling intermediates.…”

Section: Discussionmentioning

confidence: 99%

“…[136][137][138][139] Separate studies suggested that prolactin stimulates mTOR, and modifies STAT1 activity in mTOR-dependent fashion. 140,141 Further studies are required to better understand how mTORCs interact with androgen or estrogen signaling pathways.…”

Section: Other Emerging Mtor Targets In Lammentioning

confidence: 99%

mTOR Signaling in Lymphangioleiomyomatosis

Kristof

2010

Lymphatic Research and Biology

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The protein mammalian target of rapamycin (mTOR) plays a central role in cell growth and proliferation. Excessive mTOR activity is a prominent feature of many neoplasms and hamartoma syndromes, including lymphangioleiomyomatosis (LAM), a destructive lung disease that causes progressive respiratory failure in women. Although pharmacological inhibitors of mTOR should directly target the pathogenesis of these disorders, their clinical efficacy has been suboptimal. Recent scientific findings reviewed here have greatly improved our understanding of mTOR signaling mechanisms, provided new insights into the control of cell growth and proliferation, and facilitated the development of new therapeutic approaches in LAM, as well as other neoplastic disorders that exhibit excessive mTOR activity.

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“…33 Estrogen treatment of Tsc2-null ELT3 cells or TSC2-null LAMassociated angiomyolipoma cells is associated with strong and rapid (5 min) ERK-1=2 activation, suggesting that estrogen may have cytoplasmic ''nongenomic'' effects on LAM cells as well as genomic effects. [34][35][36] An interaction between tuberin and the estrogen receptor has been observed, [35][36][37] although its role in LAM pathogenesis remains unknown.…”

Section: Estrogen Promotes the Survival And Metastasis Of Tsc2-null Cmentioning

confidence: 99%

mTOR Activation, Lymphangiogenesis, and Estrogen-Mediated Cell Survival: The “Perfect Storm” of Pro-Metastatic Factors in LAM Pathogenesis

Henske

2010

Lymphatic Research and Biology

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Research interest in lymphangioleiomyomatosis (LAM) has grown dramatically in the past decade, particularly among cancer biologists. There are at least two reasons for this: first, the discovery in the year 2000 that LAM cells carry TSC2 gene mutations, linking LAM with cellular pathways including the PI3K=Akt=mTOR axis, and allowing the Tuberous Sclerosis Complex (TSC)-regulated pathways that are believed to underlie LAM pathogenesis to be studied in cells, yeast, Drosophila, and mice. A second reason for the rising interest in LAM is the discovery that LAM cells can travel to the lung, including repopulating a donor lung after lung transplantation, despite the fact that LAM cells are histologically benign. This ''benign metastasis'' underpinning suggests that elucidating LAM pathogenesis will unlock a set of fundamental mechanisms that underlie metastatic potential in the context of a cell that has not yet undergone malignant transformation. Here, we will outline the data supporting the metastatic model of LAM, consider the biochemical and cellular mechanisms that may enable LAM cells to metastasize, including both cell autonomous and non-cell autonomous factors, and highlight a mouse model in which estrogen promotes the metastasis and survival of TSC2-deficient cells in a MEKdependent manner. We propose a multistep model of LAM cell metastasis that highlights multiple opportunities for therapeutic intervention. Taken together, the metastatic behavior of LAM cells and the involvement of tumorrelated signaling pathways lead to optimism that cancer-related paradigms for diagnosis, staging, and therapy will lead to therapeutic breakthroughs for women living with LAM.

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Estrogen-induced Smooth Muscle Cell Growth Is Regulated by Tuberin and Associated with Altered Activation of Platelet-derived Growth Factor Receptor-β and ERK-1/2

Cited by 70 publications

References 56 publications

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

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

mTOR Signaling in Lymphangioleiomyomatosis

mTOR Activation, Lymphangiogenesis, and Estrogen-Mediated Cell Survival: The “Perfect Storm” of Pro-Metastatic Factors in LAM Pathogenesis

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