Beta-amyloid increases the expression level of ATBF1 responsible for death in cultured cortical neurons

Abstract

BackgroundRecently, several lines of evidence have shown the aberrant expression of cell-cycle-related proteins and tumor suppressor proteins in vulnerable neurons of the Alzheimer's disease (AD) brain and transgenic mouse models of AD; these proteins are associated with various paradigms of neuronal death. It has been reported that ATBF1 induces cell cycle arrest associated with neuronal differentiation in the developing rat brain, and that gene is one of the candidate tumor suppressor genes for prostate and breast cancers in whose cells overexpressed ATBF1 induces cell cycle arrest. However, the involvement of ATBF1 in AD pathogenesis is as yet unknown.ResultsWe found that ATBF1 was up-regulated in the brains of 17-month-old Tg2576 mice compared with those of age-matched wild-type mice. Moreover, our in vitro studies showed that Aβ1-42 and DNA-damaging drugs, namely, etoposide and homocysteine, increased the expression ATBF1 level in primary rat cortical neurons, whereas the knockdown of ATBF1 in these neurons protected against neuronal death induced by Aβ1-42, etoposide, and homocysteine, indicating that ATBF1 mediates neuronal death in response to these substances. In addition, we found that ATBF1-mediated neuronal death is dependent on ataxia-telangiectasia mutated (ATM) because the blockage of ATM activity by treatment with ATM inhibitors, caffeine and KU55933, abolished ATBF1 function in neuronal death. Furthermore, Aβ1-42 phosphorylates ATM, and ATBF1 interacts with phosphorylated ATM.ConclusionsTo the best of our knowledge, this is the first report that Aβ1-42 and DNA-damaging drugs increased the ATBF1 expression level in primary rat cortical neurons; this increase, in turn, may activate ATM signaling responsible for neuronal death through the binding of ATBF1 to phosphorylated ATM. ATBF1 may therefore be a suitable target for therapeutic intervention of AD.

Deletion of Atbf1/Zfhx3 In Mouse Prostate Causes Neoplastic Lesions, Likely by Attenuation of Membrane and Secretory Proteins and Multiple Signaling Pathways

“…The AT-motif binding factor 1/zinc finger homeobox 3 ( ATBF1 / ZFHX3 ) gene encodes a large protein structurally characterized by multiple zinc-finger motifs and four homeodomains [1] . ATBF1 appears to play a role in neuronal differentiation and cell death [2] , [3] , [4] , atrial fibrillation [5] , [6] , and embryonic development [7] . ATBF1 could be a tumor suppressor in several organs including the prostate, breast, stomach, liver, and head and neck.…”

Novel Nucleotide Variations, Haplotypes Structure and Associations with Growth Related Traits of Goat AT Motif-Binding Factor (<i>ATBF1</i>) Gene

“…As a cancer suppressor gene, ATBF1 gene not only regulates cell proliferation and differentiation ( Ninomiya et al, 2002 ; Ishii et al, 2003 ; Jung et al, 2011 ), but also interacts with PIAS3 to suppress STAT3 signaling way ( Nishio et al, 2012 ; Jiang et al, 2014 ). Most importantly, ATBF1 is necessary for the Pit1 gene activation, indicating that ATBF1 could indirectly participate in the regulative roles of Pit1 gene, including regulating Wnt/beta-catenin pathway and POU1F1 pathway ( Carvalho et al, 2006 ; Qi et al, 2008 ; Davis et al, 2010 ).…”

“…Function experiments show that ATBF1-A inhibits the enhancer of AFP and induces cell differentiation and death, while ATBF1-B promotes AFP expression by activating its enhancer ( Ninomiya et al, 2002 ; Nojiri et al, 2004 ; Jung et al, 2005 ; Sun et al, 2007 ; Cleton-Jansen et al, 2008 ; Kai et al, 2008 ). From the available studies, ATBF1 is responsible for suppressing AFP transcription by binding with its enhancer competing with hepatocyte nuclear factor-1 (HNF-1) ( Yasuda et al, 1994 ), thereby it plays an important role in cell differentiation and death ( Ishii et al, 2003 ; Jung et al, 2011 ; Perea et al, 2013 ), tumour genesis ( Sun et al, 2012 ; Sun et al, 2014 ), atrial fibrillation and embryonic development ( Benjamin et al, 2009 ; Gudbjartsson et al, 2009 ; Perea et al, 2013 ). Furthermore, ATBF1 interacts with Smads to regulate thyroid-stimulating hormone beta (TSH-β) signaling pathway ( Massagué, 2005 ; Moustakas et al, 2009 ; Massagué et al, 2012 ), thus it represses AFP expression ( Sakata et al, 2014 ).…”

Distinctive RNA Expression Profiles in Blood Associated With Alzheimer Disease After Accounting for White Matter Hyperintensities

“…The Ataxia Telangiectasia mutated gene ( ATM) is involved in controlling the cell cycle, and aberrant entry of neurons into the cell cycle has been one mechanism proposed for neuronal cell death in AD brain 33 . Aβ1–42 and DNA-damaging drugs increase ATBF1 levels in cultured neurons which activates ATM signaling responsible for neuronal death through the binding of ATBF1 to phosphorylated ATM 33 .…”

“…Aβ1–42 and DNA-damaging drugs increase ATBF1 levels in cultured neurons which activates ATM signaling responsible for neuronal death through the binding of ATBF1 to phosphorylated ATM 33 .…”