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Mice deficient in RAX<\/jats:styled-content> show reproductive and developmental defects, including reduced body size, craniofacial defects and anterior pituitary hypoplasia. As these defects are not observed in PKR<\/jats:styled-content>\u2010deficient mice, the phenotype has been attributed to PKR<\/jats:styled-content>\u2010independent activities of RAX<\/jats:styled-content>. Here we further investigated the involvement of PKR<\/jats:styled-content> in the physiological function of RAX<\/jats:styled-content>, by generating rax<\/jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> mice deficient in PKR<\/jats:styled-content>, or carrying a kinase\u2010inactive mutant of PKR<\/jats:styled-content> (K271R) or an unphosphorylatable mutant of the PKR<\/jats:styled-content> substrate eukaryotic translation initiation factor 2 \u03b1 subunit (eIF2\u03b1) (S51A). Ablating PKR<\/jats:styled-content> expression rescued the developmental and reproductive deficiencies in rax<\/jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> mice. Generating rax<\/jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> mice with a kinase\u2010inactive mutant of PKR<\/jats:styled-content> resulted in similar rescue, confirming that the rax<\/jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> defects are PKR<\/jats:styled-content> dependent; specifically that the kinase activity of PKR<\/jats:styled-content> was required for these defects. Moreover, generating rax<\/jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> mice that were heterozygous for an unphosphorylatable mutant eIF<\/jats:styled-content>2\u03b1 provides partial rescue of the rax<\/jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> defect, consistent with mutation of one copy of the Eif2s1<\/jats:italic> gene. These observations were further investigated in vitro<\/jats:italic> by reducing RAX<\/jats:styled-content> expression in anterior pituitary cells, resulting in increased PKR<\/jats:styled-content> activity and induction of the PKR<\/jats:styled-content>\u2010regulated cyclin\u2010dependent kinase inhibitor p21WAF1\/CIP1<\/jats:sup>. These results demonstrate that PKR<\/jats:styled-content> kinase activity is required for onset of the rax<\/jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> phenotype, implying an unexpected function for RAX<\/jats:styled-content> as a negative regulator of PKR<\/jats:styled-content> in the context of postnatal anterior pituitary tissue, and identify a critical role for the regulation of PKR<\/jats:styled-content> activity for normal development.<\/jats:p>","DOI":"10.1111\/febs.13533","type":"journal-article","created":{"date-parts":[[2015,9,28]],"date-time":"2015-09-28T19:13:00Z","timestamp":1443467580000},"page":"4766-4781","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["The protein activator of protein kinase R, PACT<\/scp>\/RAX<\/scp>, negatively regulates protein kinase R during mouse anterior pituitary development"],"prefix":"10.1111","volume":"282","author":[{"given":"Benjamin K.","family":"Dickerman","sequence":"first","affiliation":[{"name":"Department of Molecular Genetics Lerner Research Institute Cleveland Clinic OH USA"},{"name":"Graduate Program in Molecular Virology Case Western Reserve University Cleveland OH USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine L.","family":"White","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics Lerner Research Institute Cleveland Clinic OH USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia M.","family":"Kessler","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics Lerner Research Institute Cleveland Clinic OH USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony J.","family":"Sadler","sequence":"additional","affiliation":[{"name":"Centre for Cancer Research Hudson Institute of Medical Research Clayton Victoria Australia"},{"name":"Department of Molecular and Translational Science Monash University Clayton Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bryan R. 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