Cross-talk between tuberin, calmodulin, and estrogen signaling pathways.
Lymphangioleiomyomatosis (LAM) is a rare disease that occurs primarily in women and has been linked to both estrogen-mediated signaling events and mutations associated with the tuberous sclerosis complex 2 gene product tuberin. These two observations fostered the hypothesis that tuberin's impact on estrogen-mediated signaling might be through a direct interaction with the intracellular receptor for estrogen, estrogen receptor alpha (ERalpha). In the study presented here, tuberin was shown to co-immunoprecipitate and directly bind ERalpha through a domain localized within the carboxyl 73 amino acids of tuberin. This domain had previously been shown to serve as a binding domain for the intracellular calcium signaling molecule calmodulin (CaM). Competition binding studies identified a potential competitive relationship for binding of tuberin by ERalpha and CaM. Additionally, tuberin-ERalpha interactions were found to be modulated by the presence of tuberin's predominant intracellular binding partner hamartin, suggesting that tuberin-hamartin interactions negatively impact the ability of tuberin to modulate ERalpha-mediated gene transcription events. Cumulatively, data presented here support the hypothesis that interactions between tuberin, ERalpha, and CaM may play a critical role in the pathology of LAM disease.
York
Brian
B
Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky 40536-0298, USA.
Lou
Dingyuan
D
Panettieri
Reynold A
RA
Krymskaya
Vera P
VP
Vanaman
Thomas C
TC
Noonan
Daniel J
DJ
D001667:Binding, Competitive; D002147:Calmodulin / Q000378:metabolism*; D004247:DNA / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000502:physiology*; D004967:Estrogens / Q000502:physiology*; D005260:Female; D006801:Humans; D018192:Lymphangioleiomyomatosis / Q000209:etiology*; D015398:Signal Transduction / Q000502:physiology*; D014158:Transcription, Genetic; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
D002147:Calmodulin; D047628:Estrogen Receptor alpha; D004967:Estrogens; C000624650:TSC1 protein, human; C000624653:TSC2 protein, human; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D004247:DNA