title: Activating Transcription Factor 4 (ATF4) modulates Rho GTPase levels and function via regulation of RhoGDIα.
abstract: In earlier studies, we showed that ATF4 down-regulation affects post-synaptic development and dendritic spine morphology in neurons through increased turnover of the Rho GTPase Cell Division Cycle 42 (Cdc42) protein. Here, we find that ATF4 down-regulation in both hippocampal and cortical neuron cultures reduces protein and message levels of RhoGDIα, a stabilizer of the Rho GTPases including Cdc42. This effect is rescued by an shATF4-resistant active form of ATF4, but not by a mutant that lacks transcriptional activity. This is, at least in part, due to the fact that Arhgdia, the gene encoding RhoGDIα, is a direct transcriptional target of ATF4 as is shown in ChIP assays. This pathway is not restricted to neurons. This is seen in an impairment of cell migration on ATF4 reduction in non-neuronal cells. In conclusion, we have identified a new cellular pathway in which ATF4 regulates the expression of RhoGDIα that in turn affects Rho GTPase protein levels, and thereby, controls cellular functions as diverse as memory and cell motility.
authors.affiliation: Department of Pathology &Cell Biology and Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Silvia
authors.initials: S
authors.lastname: Pasini
authors.affiliation: Department of Pathology &Cell Biology and Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Jin
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Pathology &Cell Biology and Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Carlo
authors.initials: C
authors.lastname: Corona
authors.affiliation: Department of Pathology &Cell Biology and Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Eugenie
authors.initials: E
authors.lastname: Peze-Heidsieck
authors.affiliation: Department of Pathology &Cell Biology and Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Shelanski
authors.affiliation: Department of Pathology &Cell Biology and Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Lloyd A
authors.initials: LA
authors.lastname: Greene
mesh_terms: D051701:Activating Transcription Factor 4 / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology* / Q000378:metabolism; D015536:Down-Regulation; D057809:HEK293 Cells; D006624:Hippocampus / Q000166:cytology* / Q000378:metabolism; D006801:Humans; D009474:Neurons / Q000378:metabolism; D051381:Rats; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism*; D062948:rho Guanine Nucleotide Dissociation Inhibitor alpha / Q000378:metabolism*
chemical_list: C497110:Atf4 protein, rat; D062948:rho Guanine Nucleotide Dissociation Inhibitor alpha; D051701:Activating Transcription Factor 4; D020764:cdc42 GTP-Binding Protein