000129041 001__ 129041
000129041 005__ 20240228143405.0
000129041 0247_ $$2doi$$a10.1172/JCI86477
000129041 0247_ $$2pmid$$apmid:27454298
000129041 0247_ $$2pmc$$apmc:PMC4966329
000129041 0247_ $$2ISSN$$a0021-9738
000129041 0247_ $$2ISSN$$a1558-8238
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000129041 037__ $$aDKFZ-2017-05046
000129041 041__ $$aeng
000129041 082__ $$a610
000129041 1001_ $$aLesina, Marina$$b0
000129041 245__ $$aRelA regulates CXCL1/CXCR2-dependent oncogene-induced senescence in murine Kras-driven pancreatic carcinogenesis.
000129041 260__ $$aAnn Arbor, Mich.$$bASCJ$$c2016
000129041 3367_ $$2DRIVER$$aarticle
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000129041 520__ $$aTumor suppression that is mediated by oncogene-induced senescence (OIS) is considered to function as a safeguard during development of pancreatic ductal adenocarcinoma (PDAC). However, the mechanisms that regulate OIS in PDAC are poorly understood. Here, we have determined that nuclear RelA reinforces OIS to inhibit carcinogenesis in the Kras mouse model of PDAC. Inactivation of RelA accelerated pancreatic lesion formation in Kras mice by abrogating the senescence-associated secretory phenotype (SASP) gene transcription signature. Using genetic and pharmacological tools, we determined that RelA activation promotes OIS via elevation of the SASP factor CXCL1 (also known as KC), which activates CXCR2, during pancreatic carcinogenesis. In Kras mice, pancreas-specific inactivation of CXCR2 prevented OIS and was correlated with increased tumor proliferation and decreased survival. Moreover, reductions in CXCR2 levels were associated with advanced neoplastic lesions in tissue from human pancreatic specimens. Genetically disabling OIS in Kras mice caused RelA to promote tumor proliferation, suggesting a dual role for RelA signaling in pancreatic carcinogenesis. Taken together, our data suggest a pivotal role for RelA in regulating OIS in preneoplastic lesions and implicate the RelA/CXCL1/CXCR2 axis as an essential mechanism of tumor surveillance in PDAC.
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000129041 650_7 $$2NLM Chemicals$$aChemokine CXCL1
000129041 650_7 $$2NLM Chemicals$$aCxcl1 protein, mouse
000129041 650_7 $$2NLM Chemicals$$aRNA, Messenger
000129041 650_7 $$2NLM Chemicals$$aReceptors, Interleukin-8B
000129041 650_7 $$2NLM Chemicals$$aRela protein, mouse
000129041 650_7 $$2NLM Chemicals$$aTranscription Factor RelA
000129041 650_7 $$0EC 3.6.5.2$$2NLM Chemicals$$aras Proteins
000129041 7001_ $$aWörmann, Sonja Maria$$b1
000129041 7001_ $$aMorton, Jennifer$$b2
000129041 7001_ $$aDiakopoulos, Kalliope Nina$$b3
000129041 7001_ $$aKorneeva, Olga$$b4
000129041 7001_ $$aWimmer, Margit$$b5
000129041 7001_ $$aEinwächter, Henrik$$b6
000129041 7001_ $$aSperveslage, Jan$$b7
000129041 7001_ $$aDemir, Ihsan Ekin$$b8
000129041 7001_ $$0P:(DE-He78)d62b83b4d50fc81a7b45d3a16a47ddf0$$aKehl, Timo$$b9$$udkfz
000129041 7001_ $$aSaur, Dieter$$b10
000129041 7001_ $$aSipos, Bence$$b11
000129041 7001_ $$0P:(DE-He78)66ed2d4ec9bc11d29b87ac006adf85e5$$aHeikenwälder, Mathias$$b12$$udkfz
000129041 7001_ $$aSteiner, Jörg Manfred$$b13
000129041 7001_ $$aWang, Timothy Cragin$$b14
000129041 7001_ $$aSansom, Owen J$$b15
000129041 7001_ $$aSchmid, Roland Michael$$b16
000129041 7001_ $$aAlgül, Hana$$b17
000129041 773__ $$0PERI:(DE-600)2018375-6$$a10.1172/JCI86477$$gVol. 126, no. 8, p. 2919 - 2932$$n8$$p2919 - 2932$$tThe @journal of clinical investigation$$v126$$x1558-8238$$y2016
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000129041 9141_ $$y2016
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