FIAT represses ATF4-mediated transcription to regulate bone mass in transgenic mice

Yu, Vionnie W.C.; Ambartsoumian, Gourgen; Verlinden, Lieve; Moir, J M; Prud’homme, Josée; Gauthier, Claude; Roughley, Peter J.; St‐Arnaud, René

doi:10.1083/jcb.200412139

Cited by 55 publications

(138 citation statements)

References 45 publications

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“…37 Furthermore, aNAC was reported to interact with g-taxilin, which inhibits ATF4-mediated transcription. 18,19 In this study, we showed that aNAC ablation by the RNA interference resulted in the upregulation of ATF4 and downregulation of g-taxilin (Figure 4a), consistent with the previous findings. Therefore, these studies imply that aNAC and eIF2a might coordinately regulate transcriptional and translational responses of the cell to hypoxia, thereby determining the fate of the hypoxic cell.…”

Section: Discussionsupporting

confidence: 80%

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αNAC depletion as an initiator of ER stress-induced apoptosis in hypoxia

Hotokezaka

Leyen

et al. 2009

Cell Death Differ

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Accumulation of unfolded proteins triggers endoplasmic reticulum (ER) stress and is considered a part of the cellular responses to hypoxia. The nascent polypeptide-associated complex (NAC) participates in the proper maturation of newly synthesized proteins. However, thus far, there have been no comprehensive studies on NAC involvement in hypoxic stress. Here, we show that hypoxia activates glycogen synthase kinase-3b (GSK-3b) and that the activated GSK-3b destabilizes aNAC with the subsequent apoptosis of the cell. Hypoxia of various cell types and the mouse ischemic brain was associated with rapid downregulation of aNAC and ER stress responses involving PERK, ATF4, c-taxilin, elF2a, Bip, and CHOP. Depletion of aNAC by RNA interference specifically activated ER stress responses and caused mitochondrial dysfunction, which resulted in apoptosis through caspase activation. Interestingly, we found that the hypoxic conditions activated GSK-3b, and that GSK-3b inhibition prevented aNAC protein downregulation in hypoxic cells and rescued the cells from apoptosis. In addition, aNAC overexpression increased the viability of hypoxic cells. Taken together, these results suggest that aNAC degradation triggers ER stress responses and initiates apoptotic processes in hypoxic cells, and that GSK-3b may participate upstream in this mechanism.

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Section: Discussionsupporting

confidence: 80%

“…Previous reports have shown that g-taxilin is a regulator of ATF4 activity and interacts with aNAC. 18,19 Therefore, we assessed g-taxilin protein Figure S2).…”

Section: Resultsmentioning

confidence: 99%

αNAC depletion as an initiator of ER stress-induced apoptosis in hypoxia

Hotokezaka

Leyen

et al. 2009

Cell Death Differ

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“…FIAT, a bZIP factor inhibits ATF4-mediated transcription by forming an inactive heterodimer with ATF4. Transgenic expression of FIAT with a 2.3-kb fragment of the mouse Col1a1 promoter resulted in greatly decreased trabecular bone volume and osteocalcin expression [41]. This model has interesting phenotypic similarities with ICER transgenic mice, thus strengthening our hypothesis that ATF4 is a target of ICER.…”

Section: Discussionsupporting

confidence: 52%

“…Further studies will be necessary to support these results. Recently, the factor inhibiting ATF4-mediated transcription (FIAT) was identified in osteoblasts [41]. FIAT, a bZIP factor inhibits ATF4-mediated transcription by forming an inactive heterodimer with ATF4.…”

Section: Discussionmentioning

confidence: 99%

Osteopenia in transgenic mice with osteoblast-targeted expression of the inducible cAMP early repressor

Chandhoke¹,

Huang²,

Liu³

et al. 2008

Bone

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ICER is a member of the CREM family of basic leucine zipper transcription factors that acts as a dominant negative regulator of gene transcription. Four different isoforms of ICER (I, Iγ, II and IIγ) are transcribed from the P2 promoter of the Crem gene. We previously found that each of the ICER isoforms is induced by parathyroid hormone in osteoblasts. The goal of the present study was to assess the function of ICER in bone by overexpressing ICER in osteoblasts of transgenic mice. ICER I and ICER II cDNAs, each containing an N-terminal FLAG epitope tag, were cloned downstream of a fragment containing 3.6 kb of the rat Col1a1 promoter and most of the rat Col1a1 first intron to produce pOBCol3.6-ICER I and pOBCol3.6-ICER II transgenes, respectively. Multiple lines of mice were generated bearing the ICER I and ICER II transgenes. At 8 weeks of age, ICER I and ICER II transgenic mice had lower body weights and decreased bone mineral density of femurs and vertebrae. Further studies were done with ICER I transgenic mice, which had had greatly reduced trabecular bone volume and a markedly decreased bone formation rate in femurs. Osteoblast differentiation and osteocalcin expression were reduced in ex vivo bone marrow cultures from ICER I transgenic mice. ICER I antagonized the activity of ATF4 at its consensus DNA binding site in the osteocalcin promoter in vitro. Thus, transgenic mice with osteoblast-targeted overexpression of ICER resulted in osteopenia caused primarily by reduced bone formation. We speculate that ICER regulates the activity and/or expression of ATF/CREB factors required for normal bone formation.

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“…1B). Also identified were Nrf-2 (nuclear factorerythroid 2-related factor) and factor inhibiting ATF4-mediated transcription, two proteins known to bind ATF4 (36,37). Among the positive clones obtained, five corresponded to the open reading frame of CHOP; two clones were the full-length CHOP sequence, one was the entire bZIP domain, and two were the leucine zipper domain (Fig.…”

Section: Resultsmentioning

confidence: 99%