{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,23]],"date-time":"2025-12-23T05:32:58Z","timestamp":1766467978020},"reference-count":28,"publisher":"The Endocrine Society","issue":"7","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2012,7,1]]},"abstract":"<jats:p>Reprimo (RPRM), initially identified as a downstream effector of p53-induced cell cycle arrest at G2\/M, is a putative tumor suppressor silenced in some types of cancer. In microarrays, the RPRM transcript was repressed 26-fold in gonadotrope (null cell) human pituitary tumors compared with normal pituitary but in the absence of changes in p53. Inhibition of RPRM mRNA was confirmed by RT-PCR in all gonadotrope tumors, most GH samples, and variably in other tumor types. Human pituitary tumors showed no evidence of abnormal promoter hypermethylation as a mechanism of RPRM repression. RPRM stable expression in gonadotrope (L\u03b2T2) and GH (GH3) pituitary cells resulted in decreased rates of cell proliferation by 55 and 30%, respectively; however, RPRM reexpression did not alter G2\/M transition. In addition, RPRM increased rates of apoptosis in response to growth factor deprivation as assessed by caspase-3 cleavage and nuclear condensation. Clonagenic assays showed a 5.3- and 3.7-fold suppression of colony growth in RPRM-overexpressing L\u03b2T2 and GH3 cells, respectively, supporting its role as a tumor suppressor. In cells stably expressing RPRM mRNA, protein levels were actively suppressed due to rapid degradation through ubiquitination and proteasomal targeting. Growth factor withdrawal, as a model of cellular stress, stabilized RPRM protein levels. Together these data suggest that RPRM is transiently up-regulated at a posttranscriptional level in times of cellular stress to restrict cell survival, proliferation, and tumor formation. When RPRM is silenced as in human pituitary tumors, unrestrained growth and tumor progression may occur.<\/jats:p>","DOI":"10.1210\/en.2011-2021","type":"journal-article","created":{"date-parts":[[2012,5,6]],"date-time":"2012-05-06T00:16:29Z","timestamp":1336263389000},"page":"2963-2973","source":"Crossref","is-referenced-by-count":42,"title":["Reprimo (RPRM) Is a Novel Tumor Suppressor in Pituitary Tumors and Regulates Survival, Proliferation, and Tumorigenicity"],"prefix":"10.1210","volume":"153","author":[{"given":"Mei","family":"Xu","sequence":"first","affiliation":[{"name":"Departments of Medicine, Physiology, and Biophysics (M.X., A.J.K., K.M., K.K.-V., M.E.W.), Aurora, Colorado 80045"},{"name":"Research Service (M.X., A.J.K., K.M., K.K.-V., M.E.W.), Veterans Affairs Medical Center, Denver, Colorado 80220"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aaron J.","family":"Knox","sequence":"first","affiliation":[{"name":"Departments of Medicine, Physiology, and Biophysics (M.X., A.J.K., K.M., K.K.-V., M.E.W.), Aurora, Colorado 80045"},{"name":"Research Service (M.X., A.J.K., K.M., K.K.-V., M.E.W.), Veterans Affairs Medical Center, Denver, Colorado 80220"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katherine A.","family":"Michaelis","sequence":"first","affiliation":[{"name":"Departments of Medicine, Physiology, and Biophysics (M.X., A.J.K., K.M., K.K.-V., M.E.W.), Aurora, Colorado 80045"},{"name":"Research Service (M.X., A.J.K., K.M., K.K.-V., M.E.W.), Veterans Affairs Medical Center, Denver, Colorado 80220"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katja","family":"Kiseljak-Vassiliades","sequence":"first","affiliation":[{"name":"Departments of Medicine, Physiology, and Biophysics (M.X., A.J.K., K.M., K.K.-V., M.E.W.), Aurora, Colorado 80045"},{"name":"Research Service (M.X., A.J.K., K.M., K.K.-V., M.E.W.), Veterans Affairs Medical Center, Denver, Colorado 80220"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bette K.","family":"Kleinschmidt-DeMasters","sequence":"first","affiliation":[{"name":"Pathology (B.K.K.-D.), Aurora, Colorado 80045"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kevin O.","family":"Lillehei","sequence":"first","affiliation":[{"name":"Neurosurgery (K.O.L.), University of Colorado Denver, Aurora, Colorado 80045"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Margaret E.","family":"Wierman","sequence":"first","affiliation":[{"name":"Departments of Medicine, Physiology, and Biophysics (M.X., A.J.K., K.M., K.K.-V., M.E.W.), Aurora, Colorado 80045"},{"name":"Research Service (M.X., A.J.K., K.M., K.K.-V., M.E.W.), Veterans Affairs Medical Center, Denver, Colorado 80220"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"80","published-online":{"date-parts":[[2012,5,4]]},"reference":[{"key":"2020071612214082000_B1","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1002\/cncr.20412","article-title":"The prevalence of pituitary adenomas: a systematic review.","volume":"101","author":"Ezzat","year":"2004","journal-title":"Cancer"},{"key":"2020071612214082000_B2","doi-asserted-by":"crossref","first-page":"1603","DOI":"10.1172\/JCI20401","article-title":"Mechanisms for pituitary tumorigenesis: the plastic pituitary.","volume":"112","author":"Melmed","year":"2003","journal-title":"J Clin Invest"},{"key":"2020071612214082000_B3","article-title":"Role of Reprimo in pituitary tumorigenesis","author":"Knox"},{"key":"2020071612214082000_B4","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1172\/JCI114705","article-title":"Clinically nonfunctioning pituitary tumors are monoclonal in origin.","volume":"86","author":"Alexander","year":"1990","journal-title":"J Clin Invest"},{"key":"2020071612214082000_B5","doi-asserted-by":"crossref","first-page":"195","DOI":"10.3171\/jns.2002.96.2.0195","article-title":"The long-term significance of microscopic dural invasion in 354 patients with pituitary adenomas treated with transsphenoidal surgery.","volume":"96","author":"Meij","year":"2002","journal-title":"J Neurosurg"},{"key":"2020071612214082000_B6","doi-asserted-by":"crossref","first-page":"5116","DOI":"10.1210\/jc.2003-031633","article-title":"Pituitary tumor pathogenesis\u2014the hunt for novel candidate genes continues.","volume":"88","author":"Ezzat","year":"2003","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071612214082000_B7","doi-asserted-by":"crossref","first-page":"967","DOI":"10.1210\/en.2006-0905","article-title":"Bone morphogenetic protein and retinoic acid-inducible neural specific protein-3 is expressed in gonadotrope cell pituitary adenomas and induces proliferation, migration, and invasion.","volume":"148","author":"Shorts-Cary","year":"2007","journal-title":"Endocrinology"},{"key":"2020071612214082000_B8","doi-asserted-by":"crossref","first-page":"3603","DOI":"10.1210\/en.2011-0109","article-title":"Identification of growth arrest and DNA-damage-inducible gene \u03b2 (GADD45\u03b2) as a novel tumor suppressor in pituitary gonadotrope tumors.","volume":"152","author":"Michaelis","year":"2011","journal-title":"Endocrinology"},{"key":"2020071612214082000_B9","first-page":"1262","article-title":"Loss of expression of GADD45\u03b3, a growth inhibitory gene, in human pituitary adenomas: implications for tumorigenesis.","volume":"87","author":"Zhang","year":"2002","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071612214082000_B10","doi-asserted-by":"crossref","first-page":"5119","DOI":"10.1210\/jc.2003-030222","article-title":"A pituitary-derived MEG3 isoform functions as a growth suppressor in tumor cells.","volume":"88","author":"Zhang","year":"2003","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071612214082000_B11","doi-asserted-by":"crossref","first-page":"22627","DOI":"10.1074\/jbc.C000235200","article-title":"Reprimo, a new candidate mediator of the p53-mediated cell cycle arrest at the G2 phase.","volume":"275","author":"Ohki","year":"2000","journal-title":"J Biol Chem"},{"key":"2020071612214082000_B12","doi-asserted-by":"crossref","first-page":"1803","DOI":"10.1038\/sj.onc.1204252","article-title":"Regulation of the G2\/M transition by p53.","volume":"20","author":"Taylor","year":"2001","journal-title":"Oncogene"},{"key":"2020071612214082000_B13","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1002\/ijc.21208","article-title":"Methylation status of Reprimo in head and neck carcinomas.","volume":"117","author":"Wong","year":"2005","journal-title":"Int J Cancer"},{"key":"2020071612214082000_B14","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1002\/ijc.20910","article-title":"Aberrant methylation of Reprimo in human malignancies.","volume":"115","author":"Takahashi","year":"2005","journal-title":"Int J Cancer"},{"key":"2020071612214082000_B15","doi-asserted-by":"crossref","first-page":"909","DOI":"10.1198\/016214504000000683","article-title":"A model-based background adjustment for oligonucleotide expresion arrays.","volume":"99","author":"Wu","year":"2004","journal-title":"J Am Stat Assoc"},{"key":"2020071612214082000_B16","doi-asserted-by":"crossref","first-page":"2064","DOI":"10.1210\/en.2008-1265","article-title":"Epidermal growth factor receptor pathway substrate 8 is overexpressed in human pituitary tumors: role in proliferation and survival.","volume":"150","author":"Xu","year":"2009","journal-title":"Endocrinology"},{"key":"2020071612214082000_B17","doi-asserted-by":"crossref","first-page":"6637","DOI":"10.1158\/1078-0432.CCR-06-1781","article-title":"Reprimo methylation is a potential biomarker of Barrett's-Associated esophageal neoplastic progression.","volume":"12","author":"Hamilton","year":"2006","journal-title":"Clin Cancer Res"},{"key":"2020071612214082000_B18","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1016\/j.canlet.2005.11.002","article-title":"Methylation of apoptosis related genes in the pathogenesis and prognosis of prostate cancer.","volume":"242","author":"Suzuki","year":"2006","journal-title":"Cancer Lett"},{"key":"2020071612214082000_B19","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1038\/msb4100134","article-title":"Large-scale mapping of human protein-protein interactions by mass spectrometry.","volume":"3","author":"Ewing","year":"2007","journal-title":"Mol Syst Biol"},{"key":"2020071612214082000_B20","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1016\/j.lungcan.2004.08.006","article-title":"Aberrant methylation of Reprimo in lung cancer.","volume":"47","author":"Suzuki","year":"2005","journal-title":"Lung Cancer"},{"key":"2020071612214082000_B21","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1002\/(SICI)1098-2264(199606)16:2<113::AID-GCC5>3.0.CO;2-2","article-title":"Deletion mapping of chromosome 2 in human lung carcinoma.","volume":"16","author":"Otsuka","year":"1996","journal-title":"Genes Chromosomes Cancer"},{"key":"2020071612214082000_B22","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1002\/1098-2264(2000)9999:9999<::AID-GCC1069>3.0.CO;2-6","article-title":"Identification of novel deletion regions on chromosome arms 2q and 6p in breast carcinomas by amplotype analysis.","volume":"30","author":"Piao","year":"2001","journal-title":"Genes Chromosomes Cancer"},{"key":"2020071612214082000_B23","doi-asserted-by":"crossref","first-page":"1867","DOI":"10.1097\/01.LAB.0000106723.75567.72","article-title":"Loss of heterozygosity and mutational analyses of the ACTRII gene locus in human colorectal tumors.","volume":"83","author":"Olaru","year":"2003","journal-title":"Lab Invest"},{"key":"2020071612214082000_B24","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1128\/MCB.00907-09","article-title":"Histone deacetylase 7 and FoxA1 in estrogen-mediated repression of RPRM.","volume":"30","author":"Malik","year":"2010","journal-title":"Mol Cell Biol"},{"key":"2020071612214082000_B25","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1016\/j.molcel.2006.01.020","article-title":"p53 ubiquitination: Mdm2 and beyond.","volume":"21","author":"Brooks","year":"2006","journal-title":"Mol Cell"},{"key":"2020071612214082000_B26","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1038\/387296a0","article-title":"Mdm2 promotes the rapid degradation of p53.","volume":"387","author":"Haupt","year":"1997","journal-title":"Nature"},{"key":"2020071612214082000_B27","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1038\/387299a0","article-title":"Regulation of p53 stability by Mdm2.","volume":"387","author":"Kubbutat","year":"1997","journal-title":"Nature"},{"key":"2020071612214082000_B28","doi-asserted-by":"crossref","first-page":"19488","DOI":"10.1073\/pnas.0708380104","article-title":"Tumor cell-selective regulation of NOXA by c-MYC in response to proteasome inhibition.","volume":"104","author":"Nikiforov","year":"2007","journal-title":"Proc Natl Acad Sci USA"}],"container-title":["Endocrinology"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/endo\/article-pdf\/153\/7\/2963\/8979217\/endo2963.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/endo\/article-pdf\/153\/7\/2963\/8979217\/endo2963.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,7,16]],"date-time":"2020-07-16T19:59:15Z","timestamp":1594929555000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/endo\/article\/153\/7\/2963\/2423563"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2012,5,4]]},"references-count":28,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2012,7,1]]}},"URL":"https:\/\/doi.org\/10.1210\/en.2011-2021","relation":{},"ISSN":["0013-7227","1945-7170"],"issn-type":[{"value":"0013-7227","type":"print"},{"value":"1945-7170","type":"electronic"}],"subject":[],"published":{"date-parts":[[2012,5,4]]}}}