Disease relevance of Atf4

• A frameshift mutation is present in one allele of the Atf4 gene in genomic DNA from F9 embryonal carcinoma stem cells [1].
• The lens-specific expression of ATF4 in the mutant mice led not only to the recovery of lens secondary fibres but also to the induction of hyperplasia of these fibres [2].
• Transgenic mice overexpressing FIAT/gamma-taxilin show osteopenia and reduced expression of the ATF4 target gene, osteocalcin [3].

High impact information on Atf4

• Accordingly, Atf4-deficiency results in delayed bone formation during embryonic development and low bone mass throughout postnatal life [4].
• Perk(-/-) cells, lacking an upstream ER stress-activated eIF2alpha kinase that activates Atf4, accumulate endogenous peroxides during ER stress, whereas interference with the ER oxidase ERO1 abrogates such accumulation [5].
• Atf4(-/-) cells are impaired in expressing genes involved in amino acid import, glutathione biosynthesis, and resistance to oxidative stress [5].
• We report the characterization of factor inhibiting activating transcription factor 4 (ATF4)-mediated transcription (FIAT), a leucine zipper nuclear protein [6].
• Stress-induced eukaryotic translation initiation factor 2 (eIF2) alpha phosphorylation paradoxically increases translation of the metazoan activating transcription factor 4 (ATF4), activating the integrated stress response (ISR), a pro-survival gene expression program [7].

Biological context of Atf4

• That study, however, did not address whether forced expression of Atf4 in non-osteoblastic cells would lead to osteoblast-specific gene expression, one of the most important features of a cell differentiation factor [8].
• The role of ATF4 (activating transcription factor 4) in osteoblast differentiation and bone formation was recently described using ATF4-deficient mice (Yang, X., Matsuda, K., Bialek, P., Jacquot, S., Masuoka, H. C., Schinke, T., Li, L., Brancorsini, S., Sassone-Corsi, P., Townes, T. M., Hanauer, A., and Karsenty, G. (2004) Cell 117, 387-398) [9].
• The ability of both normal and mutated Atf4 gene products to influence cell growth was tested using an NIH3T3 cell transformation assay [1].
• The mutation results in the fusion of a short 5' open reading frame to the coding sequence of Atf4, replacing the first 18 N-terminal amino acids with 50 amino acids encoded by the upstream open reading frame [1].
• Mutated Atf4 suppresses c-Ha-ras oncogene transcript levels and cellular transformation in NIH3T3 fibroblasts [1].

Anatomical context of Atf4

• To address this question we searched for cell lines that would not express Atf4 [8].
• ATF4 increased the levels of Ocn mRNA and mOG2 promoter activity in Runx2-containing osteoblasts but not in non-osteoblastic cells that lack detectable Runx2 protein [9].
• In conclusion, results presented here show that cannabinoids lead to apoptosis of pancreatic tumor cells via a CB(2) receptor and de novo synthesized ceramide-dependent up-regulation of p8 and the endoplasmic reticulum stress-related genes ATF-4 and TRB3 [10].
• Activating transcription factor 4 overexpression inhibits proliferation and differentiation of mammary epithelium resulting in impaired lactation and accelerated involution [11].
• Consistent with this defect in anterior epithelial cell survival, in situ hybridization studies showed that CREB-2 is expressed at high levels in wild-type anterior epithelial lens cells at ED 14 [12].

Associations of Atf4 with chemical compounds

• Deletion analysis showed that the leucine zipper domain of ATF4 is critical for Runx2 activation [9].

Other interactions of Atf4

• Regions within Runx2 required for ATF4 complex formation and activation were identified [9].
• Overexpression of IMPACT in mouse embryonic fibroblasts inhibited phosphorylation of eIF2alpha by GCN2 under leucine starvation conditions, abolishing expression of its downstream target genes, ATF4 (CREB-2) and CHOP (GADD153) [13].
• One of these is a bZIP protein of the ATF/CREB protein family--probably the murine homolog of TAXREB67 [14].
• Microphthalmia due to p53-mediated apoptosis of anterior lens epithelial cells in mice lacking the CREB-2 transcription factor [12].
• In addition to its own family members, ATF4 can also form heterodimers with other related but distinct bZIP proteins such as the C/EBP, AP-1 and Maf families, which may give rise to a variety of combinatorial diversity in gene regulation [2].

Analytical, diagnostic and therapeutic context of Atf4

• In this report we have used gene targeting to produce CREB-2-deficient (CREB-2-/-) mice [12].
• Gel mobility shift and chromatin immunoprecipitation assays confirm that CREB-2 binds to the site in vitro and in vivo [15].

References