title: LIM kinase 1 - dependent cofilin 1 pathway and actin dynamics mediate nuclear retinoid receptor function in T lymphocytes.
abstract: BACKGROUND
  It is known that retinoid receptor function is attenuated during T cell activation, a phenomenon that involves actin remodeling, suggesting that actin modification may play a role in such inhibition. Here we have investigated the role of actin dynamics and the effect of actin cytoskeleton modifying agents on retinoid receptor-mediated transactivation.
  
  
  RESULTS
  Agents that disturb the F-actin assembly or disassembly attenuated receptor-mediated transcription indicating that actin cytoskeletal homeostasis is important for retinoid receptor function. Overexpression or siRNA-induced knockdown of cofilin-1 (CFL1), a key regulator of F-actin assembly, induced the loss of receptor function. In addition, expression of either constitutively active or inactive/dominant-negative mutants of CFL1or CFL1 kinase LIMK1 induced loss of receptor function suggesting a critical role of the LIMK1-mediated CFL1 pathway in receptor-dependent transcription. Further evidence of the role of LMK1/CFL1-mediated actin dynamics, was provided by studying the effect of Nef, an actin modifying HIV-1 protein, on receptor function. Expression of Nef induced phosphorylation of CFL1 at serine 3 and LIMK1 at threonine 508, inhibited retinoid-receptor mediated reporter activity, and the expression of a number of genes that contain retinoid receptor binding sites in their promoters. The results suggest that the Nef-mediated inhibition of receptor function encompasses deregulation of actin filament dynamics by LIMK1 activation and phosphorylation of CFL1.
  
  
  CONCLUSIONS
  We have identified a critical role of LIMK1-mediated CFL1 pathway and actin dynamics in modulating retinoid receptor mediated function and shown that LIMK1-mediated phosphocycling of CFL1 plays a crucial role in maintaining actin homeostasis and receptor activity. We suggest that T cell activation-induced repression of nuclear receptor-dependent transactivation is in part through the modification of actin dynamics.
authors.affiliation: Laboratory of Molecular Cell Biology, SAIC-Frederick, National Cancer Institute, Frederick, MD 21702, USA. mishaq@mail.nih.gov
authors.forename: Mohammad
authors.initials: M
authors.lastname: Ishaq
authors.forename: Bor-Ruei
authors.initials: BR
authors.lastname: Lin
authors.forename: Marjorie
authors.initials: M
authors.lastname: Bosche
authors.forename: Xin
authors.initials: X
authors.lastname: Zheng
authors.forename: Jun
authors.initials: J
authors.lastname: Yang
authors.forename: Dawei
authors.initials: D
authors.lastname: Huang
authors.forename: Richard A
authors.initials: RA
authors.lastname: Lempicki
authors.forename: Angelica
authors.initials: A
authors.lastname: Aguilera-Gutierrez
authors.forename: Ven
authors.initials: V
authors.lastname: Natarajan
mesh_terms: D000199:Actins / Q000378:metabolism*; D051338:Cofilin 1 / Q000235:genetics / Q000378:metabolism*; D003599:Cytoskeleton / Q000378:metabolism; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D019169:Jurkat Cells; D054461:Lim Kinases / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013601:T-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D054311:nef Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000378:metabolism
chemical_list: D000199:Actins; D051338:Cofilin 1; D034741:RNA, Small Interfering; D018168:Receptors, Retinoic Acid; D054311:nef Gene Products, Human Immunodeficiency Virus; C514837:nef protein, Human immunodeficiency virus 1; C515892:LIMK1 protein, human; D054461:Lim Kinases