title: ATF3 induction following DNA damage is regulated by distinct signaling pathways and over-expression of ATF3 protein suppresses cells growth.
abstract: Mammalian cells have a remarkable diverse repertoire of response to genotoxic stress that damage DNA. Cellular responses to DNA damaging agents will initially exhibit gene induction, which is regulated by complex mechanism(s) and probably involves multiple signaling pathways. In this paper, we demonstrate that induction of ATF3 protein, a member of the ATF/CREB family of transcription factors, by ionizing radiation (IR) requires normal cellular p53 function. In contrast, induction of ATF3 after UV radiation (UV) or Methyl methanesulphonate (MMS) is independent of p53 status. Induction of ATF3 by DNA damage is rapid, transient, and through a transcriptional mechanism. The ATF3 promoter is induced by UV and MMS, but not by IR. In addition, ATF3 promoter can be activated by MEKK1, an upstream activator of the ERK and JNK kinase pathway, but not induced following p53 expression. Those results indicate that regulation of ATF3 induction after DNA damage utilizes both the p53-dependent and -independent pathways, and may also involve MAP kinase signaling pathways. Using the tetracycline-inducible system (tet-off), we have found that over-expression of ATF3 protein moderately suppresses cell growth. Interestingly, over-expression of ATF3 protein is able to slow down progression of cells from G1 to S phase, indicating that ATF3 protein might play a negative role in the control of cell cycle progression.
authors.affiliation: Department of Radiation Oncology, Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania PA 15213, USA.
authors.forename: Feiyue
authors.initials: F
authors.lastname: Fan
authors.forename: Shunqian
authors.initials: S
authors.lastname: Jin
authors.forename: Sally A
authors.initials: SA
authors.lastname: Amundson
authors.forename: Tong
authors.initials: T
authors.lastname: Tong
authors.forename: Wenhong
authors.initials: W
authors.lastname: Fan
authors.forename: Hongcheng
authors.initials: H
authors.lastname: Zhao
authors.forename: Xiaocheng
authors.initials: X
authors.lastname: Zhu
authors.forename: Lucia
authors.initials: L
authors.lastname: Mazzacurati
authors.forename: Xianxing
authors.initials: X
authors.lastname: Li
authors.forename: Kimberly L
authors.initials: KL
authors.lastname: Petrik
authors.forename: Albert J
authors.initials: AJ
authors.lastname: Fornace
authors.forename: Baskaran
authors.initials: B
authors.lastname: Rajasekaran
authors.forename: Qimin
authors.initials: Q
authors.lastname: Zhan
mesh_terms: D051700:Activating Transcription Factor 3; D001483:Base Sequence; D002453:Cell Cycle / Q000502:physiology; D002455:Cell Division / Q000502:physiology*; D004249:DNA Damage; D017931:DNA Primers; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D020935:MAP Kinase Signaling System; D008741:Methyl Methanesulfonate / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D011839:Radiation, Ionizing; D014157:Transcription Factors / Q000235:genetics* / Q000502:physiology / Q000528:radiation effects; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014466:Ultraviolet Rays
chemical_list: D051700:Activating Transcription Factor 3; D017931:DNA Primers; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D008741:Methyl Methanesulfonate