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Rapamycin-Insensitive Up-Regulation of MMP2 and Other Genes in Tuberous Sclerosis Complex 2–Deficient Lymphangioleiomyomatosis-Like Cells

¹ Pulmonary and Critical Care Division, ² Translational Medicine Division, and ⁴ Renal Division, Brigham and Women's Hospital, Boston, Massachusetts; ³ Vascular Biology Program, Children's Hospital, Boston, Massachusetts; ⁵ ARIAD Pharmaceuticals, Inc., Cambridge, Massachusetts; ⁶ Harvard Medical School, Boston, Massachusetts; and ⁷ Department of Biological Sciences, Virginia Polytechnic Institute and State University, Blacksburg, Virginia

Correspondence and requests for reprints should be addressed to Po-Shun Lee, M.D., 1 Blackfan Circle, Karp Research Building, 6th Floor, Brigham and Women's Hospital, Boston, MA 02115. E-mail: plee4{at}partners.org

Increased matrix metalloproteinase (MMP) activity has been implicated in the pathogenesis of lymphangioleiomyomatosis (LAM). The objective of this study was to investigate how tuberous sclerosis complex (TSC) 1 or TSC2 deficiency alters MMP expression and regulation. We studied immortalized cells that lack TSC2 derived from an angiomyolipoma of a patient with LAM, a TSC2 addback derivative, and murine embryonic fibroblast cells that lack Tsc1 or -2 and respective controls. Global gene expression analysis was performed in the angiomyolipoma and derivative cell lines. MMP levels in the conditioned media from these cells were analyzed by zymography and ELISA. We found increased MMP-2 expression in cells lacking TSC1/TSC2 compared with their respective controls by zymography. MMP-2 overproduction by these cells was not affected by rapamycin treatment. Gene expression analysis confirmed increased MMP-2 gene expression that was not affected by rapamycin. Furthermore, multiple other genes were found to be overexpressed in rapamycin-treated TSC2-deficient cells compared with TSC2⁺ cells. We conclude that TSC1/TSC2 deficiency leads to MMP-2 overproduction that is rapamycin-insensitive, and that several genes exhibit similar patterns, suggesting that TSC1/TSC2–dependent, but mammalian target of rapamycin–independent, pathways may be involved in the pathogenesis of LAM.

Key Words: interstitial collagenase • neoplasms • sirolimus

CLINICAL RELEVANCE This research provides data linking increase matrix metalloproteinase expressions in tuberous sclerosis complex (TSC)–related diseases. This report also suggests that rapamycin-insensitive pathways may be involved in TSC-related diseases.

 

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