title: Alk is a transcriptional target of LMO4 and ERα that promotes cocaine sensitization and reward.
abstract: Previously, we showed that the mouse LIM-domain only 4 (Lmo4) gene, which encodes a protein containing two zinc-finger LIM domains that interact with various DNA-binding transcription factors, attenuates behavioral sensitivity to repeated cocaine administration. Here we show that transcription of anaplastic lymphoma kinase (Alk) is repressed by LMO4 in the striatum and that Alk promotes the development of cocaine sensitization and conditioned place preference, a measure of cocaine reward. Since LMO4 is known to interact with estrogen receptor α (ERα) at the promoters of target genes, we investigated whether Alk expression might be controlled by a similar mechanism. We found that LMO4 and ERα are associated with the Alk promoter by chromatin immunoprecipitation and that Alk is an estrogen-responsive gene in the striatum. Moreover, we show that ERα knock-out mice exhibit enhanced cocaine sensitization and conditioned place preference and an increase in Alk expression in the nucleus accumbens. These data define a novel regulatory network involved in behavioral responses to cocaine. Interestingly, sex differences in several behavioral responses to cocaine in humans and rodents have been described, and estrogen is thought to mediate some of these differences. Our data suggest that estrogen regulation of Alk may be one mechanism responsible for sexually dimorphic responses to cocaine.
authors: The Ernest Gallo Clinic and Research Center, Department of Neurology, University of California, San Francisco, Emeryville, California 94608, USA. alasek@gallo.ucsf.edu
authors: Amy W
authors: AW
authors: Lasek
authors: Julie
authors: J
authors: Gesch
authors: Francesco
authors: F
authors: Giorgetti
authors: Viktor
authors: V
authors: Kharazia
authors: Ulrike
authors: U
authors: Heberlein
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis* / Q000235:genetics; D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D003042:Cocaine / Q000378:metabolism / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000096:biosynthesis* / Q000235:genetics; D018390:Gene Targeting / Q000379:methods*; D057809:HEK293 Cells; D006801:Humans; D060588:LIM Domain Proteins / Q000096:biosynthesis* / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D020794:Receptor Protein-Tyrosine Kinases / Q000096:biosynthesis* / Q000235:genetics; D012201:Reward; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D047628:Estrogen Receptor alpha; D060588:LIM Domain Proteins; C491976:Lmo4 protein, mouse; C000626173:ALK protein, human; C000626174:Alk protein, mouse; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases; D003042:Cocaine