Molecular pathogenesis of lymphangioleiomyomatosis: lessons learned from orphans.
Lymphangioleiomyomatosis (LAM) is a rare progressive cystic lung disease affecting young women. The pivotal observation that LAM occurs both spontaneously and as part of the tuberous sclerosis complex (TSC) led to the hypothesis that these disorders share common genetic and pathogenetic mechanisms. In this review we describe the evolution of our understanding of the molecular and cellular basis of LAM and TSC, beginning with the discovery of the TSC1 and TSC2 genes and the demonstration of their involvement in sporadic (non-TSC) LAM. This was followed by rapid delineation of the signaling pathways in Drosophila melanogaster with confirmation in mice and humans. This knowledge served as the foundation for novel therapeutic approaches that are currently being used in human clinical trials.
Juvet
Stephen C
SC
National Jewish Medical and Research Center, 1400 Jackson Street, Denver, CO 80206, USA.
McCormack
Francis X
FX
Kwiatkowski
David J
DJ
Downey
Gregory P
GP
D000818:Animals; D004331:Drosophila melanogaster / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D018192:Lymphangioleiomyomatosis / Q000209:etiology* / Q000235:genetics / Q000628:therapy; D051379:Mice; D008954:Models, Biological; D032389:Myocytes, Smooth Muscle / Q000473:pathology; D015398:Signal Transduction; D014402:Tuberous Sclerosis / Q000235:genetics; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000378:metabolism / Q000502:physiology
C000624650:TSC1 protein, human; C000624653:TSC2 protein, human; C000624651:Tsc1 protein, mouse; C000624654:Tsc2 protein, mouse; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins