原题
Identificationofmembranetype-1matrixmetalloproteinaseasatargetofhypoxia-inducIBLefactor-2[alpha]invonHippel-Lindaurenalcellcarcinoma.[Article]
来源
Oncogene.24(6):1043-1052,February3,2005.
AccessionNumber
00006374-200524060-00010.
Author
Petrella,BrendaL1;Lohi,Jouko3;Brinckerhoff,ConstanceE*,1,2
Institution
(1)DepartmentofBiochemistry,NorrisCottonCancerCenter,DartmouthMedicalSchool,Lebanon,NH03756,USA;(2)DepartmentofMedicine,NorrisCottonCancerCenter,DartmouthMedicalSchool,Lebanon,NH03756,USA;(3)DepartmentofPathology,HaartmanInstitute,UniversityofHelsinkiandHelsinkiUniversityCentralHospital,Helsinki,FIN-00014,Finland
摘要原文
Metastaticrenalcellcarcinoma(RCC)resultingfromthehereditarylossofthevonHippel-Lindau(VHL)tumorsuppressorgeneistheleADIngcauseofdeathinVHLpatientsduetothedeleteriouseffectsofthemetastatictumor(s).VHLfunctionsinthedestructionofthealphasubunitsoftheheterodimerictranscriptionfactor,hypoxia-induciblefactor(HIF-1[alpha]andHIF-2[alpha]),innormoxicconditions.WhenVHLfunctionislost,HIF-[alpha]proteinisstABIlized,andtargethypoxia-induciblegenesaretranscribed.Theprocessoftumorinvasionandmetastasisinvolvesthedestructionoftheextracellularmatrix,whichisaccomplishedprimarilybythematrixmetalloproteinase(MMP)familyofenzymes.Here,wedescribeaconnectionbetweenthelossofVHLtumorsuppressorfunctionandtheupregulationofmembranetype-1MMP(MT1-MMP)geneexpressionandprotein.Specifically,MT1-MMPisupregulatedinVHL-/-RCCcellsthroughanincreaseingenetranscription,whichismediatedbythecooperativeeffectsofthetranscriptionfactors,HIF-2andSp1.Further,weidentifyafunctionalHIF-bindingsiteintheproximalpromoterofMT1-MMP.Toourknowledge,thisisthefirstreporttoshowdirectregulationofMT1-MMPbyHIF-2andtoprovideadirectlinkbetweenthelossofVHLtumorsuppressorfunctionandanincreaseinMMPgeneandproteinexpression.
编译
vonHippel-Lindau(VHL)肿瘤抑制基因遗传性丢失引起的转移性肾细胞癌（RCC）在VHL病人中导致死亡的原因是转移性瘤的有害作用。在含氧正常情况下，VHL作用是破坏异二聚转录因子和缺氧诱导因子（HIF-1[a]和HIF-2[a]）的a亚基。当VHL作用丧失后，HIF[a]蛋白变的稳定，并且靶缺氧诱导基因被转录。肿瘤侵入和转移的过程包括细胞外基质的破坏—主要通过基质金属蛋白酶（MMP）家族的酶完成。研究者阐明了VHL肿瘤抑制功能的丧失与I型膜基质金属蛋白酶（MT1—MMP）基因表达和蛋白质之间的联系。基因转录的增加使VHL-/-RCC细胞中MT1—MMP发生向上调节，这一作用是转录因子HIF-2[a]及sp1共同作用的结果。据称，这份论文首次报道HIF-2调节了MT1-MMP，并且提出VHL肿瘤抑制功能与MMP基因表达和蛋白质表达之间具有直接的联系。