{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T19:56:16Z","timestamp":1790970976392,"version":"4.1.0"},"reference-count":37,"publisher":"National Academy of Sciences","issue":"5","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2001,2,27]]},"abstract":"<jats:p>\n                    FKBP12, the 12-kDa FK506-binding protein, is a ubiquitous abundant\n protein that acts as a receptor for the immunosuppressant drug FK506,\n binds tightly to intracellular calcium release channels and to the\n transforming growth factor \u03b2 (TGF-\u03b2) type I receptor. We now\n demonstrate that cells from FKBP12-deficient (FKBP12\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    )\n mice manifest cell cycle arrest in G\n                    <jats:sub>1<\/jats:sub>\n                    phase and that these\n cells can be rescued by FKBP12 transfection. This arrest is mediated by\n marked augmentation of p21(WAF1\/CIP1) levels, which cannot be\n further augmented by TGF-\u03b21. The p21 up-regulation and cell cycle\n arrest derive from the overactivity of TGF-\u03b2 receptor signaling,\n which is normally inhibited by FKBP12. Cell cycle arrest is prevented\n by transfection with a dominant-negative TGF-\u03b2 receptor construct.\n TGF-\u03b2 receptor signaling to gene expression can be mediated by SMAD,\n p38, and ERK\/MAP kinase (extracellular signal-regulated\n kinase\/mitogen-activated protein kinase) pathways. SMAD\n signaling is down-regulated in FKBP12\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    cells.\n Inhibition of ERK\/MAP kinase fails to affect p21 up-regulation.\n By contrast, activated phosphorylated p38 is markedly augmented in\n FKBP12\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    cells and the p21 up-regulation is prevented by\n an inhibitor of p38. Thus, FKBP12 is a physiologic regulator of cell\n cycle acting by normally down-regulating TGF-\u03b2 receptor signaling.\n                  <\/jats:p>","DOI":"10.1073\/pnas.041614198","type":"journal-article","created":{"date-parts":[[2002,7,26]],"date-time":"2002-07-26T10:45:09Z","timestamp":1027680309000},"page":"2425-2430","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":131,"title":["FKBP12, the 12-kDa FK506-binding protein, is a physiologic regulator of the cell cycle"],"prefix":"10.1073","volume":"98","author":[{"given":"Bahman","family":"Aghdasi","sequence":"first","affiliation":[{"name":"Departments of Neuroscience, Pharmacology and\r Molecular Sciences, Psychiatry, and\r Neurology, Johns Hopkins University School of Medicine,\r 725 North Wolfe Street, Baltimore, MD 21205"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keqiang","family":"Ye","sequence":"additional","affiliation":[{"name":"Departments of Neuroscience, Pharmacology and\r Molecular Sciences, Psychiatry, and\r Neurology, Johns Hopkins University School of Medicine,\r 725 North Wolfe Street, Baltimore, MD 21205"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam","family":"Resnick","sequence":"additional","affiliation":[{"name":"Departments of Neuroscience, Pharmacology and\r Molecular Sciences, Psychiatry, and\r Neurology, Johns Hopkins University School of Medicine,\r 725 North Wolfe Street, Baltimore, MD 21205"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alex","family":"Huang","sequence":"additional","affiliation":[{"name":"Departments of Neuroscience, Pharmacology and\r Molecular Sciences, Psychiatry, and\r Neurology, Johns Hopkins University School of Medicine,\r 725 North Wolfe Street, Baltimore, MD 21205"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyo Chol","family":"Ha","sequence":"additional","affiliation":[{"name":"Departments of Neuroscience, Pharmacology and\r Molecular Sciences, Psychiatry, and\r Neurology, Johns Hopkins University School of Medicine,\r 725 North Wolfe Street, Baltimore, MD 21205"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Guo","sequence":"additional","affiliation":[{"name":"Departments of Neuroscience, Pharmacology and\r Molecular Sciences, Psychiatry, and\r Neurology, Johns Hopkins University School of Medicine,\r 725 North Wolfe Street, Baltimore, MD 21205"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ted M.","family":"Dawson","sequence":"additional","affiliation":[{"name":"Departments of Neuroscience, Pharmacology and\r Molecular Sciences, Psychiatry, and\r Neurology, Johns Hopkins University School of Medicine,\r 725 North Wolfe Street, Baltimore, MD 21205"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valina L.","family":"Dawson","sequence":"additional","affiliation":[{"name":"Departments of Neuroscience, Pharmacology and\r Molecular Sciences, Psychiatry, and\r Neurology, Johns Hopkins University School of Medicine,\r 725 North Wolfe Street, Baltimore, MD 21205"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Solomon H.","family":"Snyder","sequence":"additional","affiliation":[{"name":"Departments of Neuroscience, Pharmacology and\r Molecular Sciences, Psychiatry, and\r Neurology, Johns Hopkins University School of Medicine,\r 725 North Wolfe Street, Baltimore, MD 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