{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T20:09:17Z","timestamp":1791317357702,"version":"4.3.1"},"reference-count":39,"publisher":"National Academy of Sciences","issue":"17","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2013,4,23]]},"abstract":"<jats:p>\n                    Cellular differentiation leading to formation of the bradyzoite tissue cyst stage is the underlying cause of chronic toxoplasmosis. Consequently, mechanisms responsible for controlling development in the\n                    <jats:italic>Toxoplasma<\/jats:italic>\n                    intermediate life cycle have long been sought. Here, we identified 15\n                    <jats:italic>Toxoplasma<\/jats:italic>\n                    mRNAs induced in early bradyzoite development that encode proteins with apicomplexan AP2 (ApiAP2) DNA binding domains. Of these 15 mRNAs, the AP2IX-9 mRNA demonstrated the largest expression increase during alkaline-induced differentiation. At the protein level, we found that AP2IX-9 was restricted to the early bradyzoite nucleus and is repressed in tachyzoites and in mature bradyzoites from 30-d infected animals. Conditional overexpression of AP2IX-9 significantly reduced tissue cyst formation and conferred alkaline pH-resistant growth, whereas disruption of the\n                    <jats:italic>AP2IX-9<\/jats:italic>\n                    gene increased tissue cyst formation, indicating AP2IX-9 operates as a repressor of bradyzoite development. Consistent with a role as a repressor, AP2IX-9 specifically inhibited the expression of bradyzoite mRNAs, including the canonical bradyzoite marker, bradyzoite antigen 1 (BAG1). Using protein binding microarrays, we established the AP2 domain of AP2IX-9 binds a CAGTGT DNA sequence motif and is capable of binding\n                    <jats:italic>cis<\/jats:italic>\n                    -regulatory elements controlling the BAG1 and bradyzoite-specific nucleoside triphosphatase (B-NTPase) promoters. The effect of AP2IX-9 on BAG1 expression was direct because this factor inhibits expression of a firefly luciferase reporter under the control of the BAG1 promoter in vivo, and epitope-tagged AP2IX-9 can be immunoprecipitated with the BAG1 promoter in parasite chromatin. Altogether, these results indicate AP2IX-9 restricts\n                    <jats:italic>Toxoplasma<\/jats:italic>\n                    commitment to develop the mature bradyzoite tissue cyst.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1300059110","type":"journal-article","created":{"date-parts":[[2013,4,9]],"date-time":"2013-04-09T22:18:24Z","timestamp":1365545904000},"page":"6871-6876","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":154,"title":["ApiAP2 transcription factor restricts development of the\n                    <i>Toxoplasma<\/i>\n                    tissue cyst"],"prefix":"10.1073","volume":"110","author":[{"given":"Joshua B.","family":"Radke","sequence":"first","affiliation":[{"name":"Departments of Molecular Medicine and Global Health, University of South Florida, Tampa, FL 33612;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivier","family":"Lucas","sequence":"additional","affiliation":[{"name":"Departments of Molecular Medicine and Global Health, University of South Florida, Tampa, FL 33612;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erandi K.","family":"De Silva","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"YanFen","family":"Ma","sequence":"additional","affiliation":[{"name":"Departments of Medicine and Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"Jr.","given":"William J.","family":"Sullivan","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN 46202"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louis M.","family":"Weiss","sequence":"additional","affiliation":[{"name":"Departments of Medicine and Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuel","family":"Llinas","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael W.","family":"White","sequence":"additional","affiliation":[{"name":"Departments of Molecular Medicine and Global Health, University of South Florida, Tampa, FL 33612;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2013,4,9]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"crossref","first-page":"1767","DOI":"10.2460\/javma.1970.157.11.1767","article-title":"Toxoplasma gondii life cycle in cats","volume":"157","author":"Dubey JP","year":"1970","unstructured":"JP Dubey, NL Miller, JK Frenkel, Toxoplasma gondii life cycle in cats. 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