{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T12:38:23Z","timestamp":1788871103120,"version":"build-2803163510"},"reference-count":66,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2014,11,10]],"date-time":"2014-11-10T00:00:00Z","timestamp":1415577600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"NIH","award":["NS041202"],"award-info":[{"award-number":["NS041202"]}]},{"name":"NIH","award":["NS043994"],"award-info":[{"award-number":["NS043994"]}]},{"name":"NIH","award":["NS074942"],"award-info":[{"award-number":["NS074942"]}]},{"name":"NIH","award":["NS071787"],"award-info":[{"award-number":["NS071787"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Journal of Neurochemistry"],"published-print":{"date-parts":[[2015,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    The transcription factor E2F1 activates gene targets required for G\n                    <jats:sub>1<\/jats:sub>\n                    \u2010S phase progression and for apoptosis, and exhibits increased expression levels in neurons in several\n                    <jats:styled-content style=\"fixed-case\">CNS<\/jats:styled-content>\n                    diseases including\n                    <jats:styled-content style=\"fixed-case\">HIV<\/jats:styled-content>\n                    encephalitis, Alzheimer disease, and Parkinson's Disease. While E2F1 is known to regulate cell viability through activation of caspases, here we present evidence supporting the involvement of E2F1 in\n                    <jats:italic>N<\/jats:italic>\n                    \u2010methyl\u2010\n                    <jats:sc>d<\/jats:sc>\n                    \u2010aspartate (\n                    <jats:styled-content style=\"fixed-case\">NMDA<\/jats:styled-content>\n                    ) receptor\u2010dependent,\n                    <jats:styled-content style=\"fixed-case\">HIV<\/jats:styled-content>\n                    \u2010induced neuronal death mediated by calpains. Using an\n                    <jats:italic>in vitro<\/jats:italic>\n                    model of\n                    <jats:styled-content style=\"fixed-case\">HIV<\/jats:styled-content>\n                    \u2010induced neurotoxicity that is dependent on\n                    <jats:styled-content style=\"fixed-case\">NMDA<\/jats:styled-content>\n                    receptor and calpain activation, we have shown that cortical neurons lacking functional E2F1 are less susceptible to neuronal death. In addition, we report that neuronal E2F1 is cleaved by calpain to a stable 55\u2010kiloDalton fragment following\n                    <jats:styled-content style=\"fixed-case\">NR<\/jats:styled-content>\n                    2B\u2010dependent\n                    <jats:styled-content style=\"fixed-case\">NMDA<\/jats:styled-content>\n                    receptor stimulation. This cleavage of E2F1 is protein conformation\u2010dependent and involves at least two cleavage events, one at each terminus of the protein. Intriguingly, the stabilized E2F1 cleavage product is produced in post\u2010mitotic neurons of all ages, but fails to be stabilized in cycling cells. Finally, we show that a matching E2F1 cleavage product is produced in human fetal neurons, suggesting that calpain cleavage of E2F1 may be produced in human cortical tissue. These results suggest neuronal E2F1 is processed in a novel manner in response to\n                    <jats:styled-content style=\"fixed-case\">NMDA<\/jats:styled-content>\n                    receptor\u2010mediated toxicity, a mechanism implicated in HIV\u2010associated neurocognitive disorders pathogenesis as well as several other diseases of the\n                    <jats:styled-content style=\"fixed-case\">CNS<\/jats:styled-content>\n                    .\n                    <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                      <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc12956-fig-0009-m.png\">\n                        <jats:alt-text>image<\/jats:alt-text>\n                      <\/jats:graphic>\n                    <\/jats:boxed-text>\n                  <\/jats:p>\n                  <jats:p>\n                    After crossing the blood\u2013brain barrier, HIV\u2010infected monocytes differentiate into macrophages and release excitotoxins and inflammatory factors including glutamate into the brain parenchyma (1). These factors stimulate neuronal\n                    <jats:italic>N<\/jats:italic>\n                    \u2010Methyl\u2010\n                    <jats:sc>d<\/jats:sc>\n                    \u2010aspartate (NMDA) receptors (2), causing calcium influx (3) and subsequent activation of the cysteine protease calpain (4). Activated calpain cleaves multiple substrates including E2F1, producing a stabilized protein fragment with truncations at the N\u2010 and C\u2010terminus (5). Calpain\u2010cleaved E2F1 may contribute to calpain\u2010mediated neuronal damage observed in NMDA receptor\u2010mediated neurotoxicity (6).\n                  <\/jats:p>","DOI":"10.1111\/jnc.12956","type":"journal-article","created":{"date-parts":[[2014,10,3]],"date-time":"2014-10-03T12:03:34Z","timestamp":1412337814000},"page":"742-755","source":"Crossref","is-referenced-by-count":13,"title":["E2F1 in neurons is cleaved by calpain in an\n                    <scp>NMDA<\/scp>\n                    receptor\u2010dependent manner in a model of\n                    <scp>HIV<\/scp>\n                    \u2010induced neurotoxicity"],"prefix":"10.1111","volume":"132","author":[{"given":"Jacob W.","family":"Zyskind","sequence":"first","affiliation":[{"name":"Department of Pathology School of Dental Medicine University of Pennsylvania Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pathology School of Dental Medicine University of Pennsylvania Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giyong","family":"Cho","sequence":"additional","affiliation":[{"name":"Department of Pathology School of Dental Medicine University of Pennsylvania Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jenhao H.","family":"Ting","sequence":"additional","affiliation":[{"name":"Department of Pathology School of Dental Medicine University of Pennsylvania Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dennis L.","family":"Kolson","sequence":"additional","affiliation":[{"name":"Department of Neurology The Perelman School of Medicine University of Pennsylvania Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David R.","family":"Lynch","sequence":"additional","affiliation":[{"name":"Division of Neurology Children's Hospital of Philadelphia Philadelphia Pennsylvania USA"},{"name":"Department of Neurology University of Pennsylvania Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelly L.","family":"Jordan\u2010Sciutto","sequence":"additional","affiliation":[{"name":"Department of Pathology School of Dental Medicine University of Pennsylvania Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2014,11,10]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2007.01.016"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mcn.2011.04.001"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.92.8.3110"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4247-12.2013"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M003763200"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.76.18.9407-9419.2002"},{"key":"e_1_2_7_8_1","first-page":"739","article-title":"Distinct and overlapping roles for E2F family members in transcription, proliferation and apoptosis","volume":"6","author":"DeGregori J.","year":"2006","journal-title":"Curr. Mol. Med."},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0019035"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2009.12.011"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.22-12-04842.2002"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M401267200"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.mp.4002017"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.275.16.11553"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.16-10-03139.1996"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/nri1527"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.13.10.6501"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.93.8.3362"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0611671104"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1471-4159.2001.00402.x"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.272.31.19248"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ceb.2007.10.006"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.4161\/cc.6.17.4650"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)64561-0"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0047-6374(01)00334-7"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.22-06-02185.2002"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M503259200"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.1101\/lm.1275709"},{"key":"e_1_2_7_29_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.270.29.17306"},{"key":"e_1_2_7_30_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.2012.07859.x"},{"key":"e_1_2_7_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0361-9230(00)00447-0"},{"key":"e_1_2_7_32_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M308454200"},{"key":"e_1_2_7_33_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M102067200"},{"key":"e_1_2_7_34_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0765.2011.01394.x"},{"key":"e_1_2_7_35_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.13.12.7813"},{"key":"e_1_2_7_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2008.05.004"},{"key":"e_1_2_7_37_1","first-page":"e00051","article-title":"Dual vulnerability of tau to calpains and caspase\u20103 proteolysis under neurotoxic and neurodegenerative conditions","volume":"3","author":"Liu M. C.","year":"2011","journal-title":"ASN Neuro"},{"key":"e_1_2_7_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2007.01.014"},{"key":"e_1_2_7_39_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2840-13.2014"},{"key":"e_1_2_7_40_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.410320304"},{"key":"e_1_2_7_41_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.410420618"},{"key":"e_1_2_7_42_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.22.10.3527-3536.2002"},{"key":"e_1_2_7_43_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4617-05.2006"},{"key":"e_1_2_7_44_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M001725200"},{"key":"e_1_2_7_45_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1125-05.2005"},{"key":"e_1_2_7_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1097-2765(00)80387-1"},{"key":"e_1_2_7_47_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1008652107"},{"key":"e_1_2_7_48_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)63879-5"},{"key":"e_1_2_7_49_1","doi-asserted-by":"publisher","DOI":"10.3233\/JAD-2001-3403"},{"key":"e_1_2_7_50_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2339-09.2009"},{"key":"e_1_2_7_51_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.2012.07735.x"},{"key":"e_1_2_7_52_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.14-06-03934.1994"},{"key":"e_1_2_7_53_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1097-2765(00)80310-X"},{"key":"e_1_2_7_54_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.90.7.2628"},{"key":"e_1_2_7_55_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcb.20574"},{"key":"e_1_2_7_56_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M005103200"},{"key":"e_1_2_7_57_1","doi-asserted-by":"publisher","DOI":"10.1111\/jnc.12655"},{"key":"e_1_2_7_58_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M313873200"},{"key":"e_1_2_7_59_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/24.21.4139"},{"key":"e_1_2_7_60_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12035-008-8036-x"},{"key":"e_1_2_7_61_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M410493200"},{"key":"e_1_2_7_62_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.2007.04746.x"},{"key":"e_1_2_7_63_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neulet.2010.05.032"},{"key":"e_1_2_7_64_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3293-13.2013"},{"key":"e_1_2_7_65_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neures.2011.01.013"},{"key":"e_1_2_7_66_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0912558106"},{"key":"e_1_2_7_67_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2012.07.004"}],"container-title":["Journal of Neurochemistry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fjnc.12956","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fjnc.12956","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/jnc.12956","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,4]],"date-time":"2023-10-04T23:31:59Z","timestamp":1696462319000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/jnc.12956"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,11,10]]},"references-count":66,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2015,3]]}},"alternative-id":["10.1111\/jnc.12956"],"URL":"https:\/\/doi.org\/10.1111\/jnc.12956","archive":["Portico"],"relation":{},"ISSN":["0022-3042","1471-4159"],"issn-type":[{"value":"0022-3042","type":"print"},{"value":"1471-4159","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,11,10]]}}}