Absence of the Birt-Hogg-Dubé gene product is associated with increased hypoxia-inducible factor transcriptional activity and a loss of metabolic flexibility.
Absence of the Birt-Hogg-Dubé gene product is associated with increased hypoxia-inducible factor transcriptional activity and a loss of metabolic flexibility.
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DOI：
10.1038/onc.2010.497
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发表时间：
2011-03-10
期刊：
影响因子：
8
通讯作者：
Tee, A. R.
中科院分区：
文献类型：
--
作者：
Preston, R. S.;Philp, A.;Claessens, T.;Gijezen, L.;Dydensborg, A. B.;Dunlop, E. A.;Harper, K. T.;Brinkhuizen, T.;Menko, F. H.;Davies, D. M.;Land, S. C.;Pause, A.;Baar, K.;van Steensel, M. A. M.;Tee, A. R.
在组织氧合降低的条件下，缺氧诱导因子（HIF）控制着许多过程，包括血管生成和细胞代谢，也影响细胞增殖和生存决策。HIF主要参与导致肾细胞癌（RCC）的遗传性疾病（如Von Hippel-Lindau综合征和结节性硬化症）的肿瘤生长。在这项研究中，我们研究了HIF是否参与birt - hogg - dub<s:1>综合征RCC的肿瘤形成。为此，我们分析了birt - hogg - dub<s:1>患者来源的肾肿瘤细胞系（UOK257），该细胞系缺乏birt - hogg - dub<s:1>蛋白（BHD），并观察到高水平的HIF活性。BHD表达的下调也导致HIF的三倍激活，这不是HIF1α或HIF2α蛋白增加的结果。HIF靶基因VEGF、BNIP3和CCND1的转录也升高。我们发现来自birt - hogg - dub<s:1>患者的厌色癌中HIF1α的核定位和VEGF、BNIP3和GLUT1的表达增加。我们的数据还显示，UOK257细胞具有较高的乳酸脱氢酶、丙酮酸激酶和3-羟基酰基辅酶a脱氢酶活性。我们观察到丙酮酸脱氢酶激酶1 （HIF基因靶点）的表达增加，这反过来导致丙酮酸脱氢酶的磷酸化和抑制增加。随着GLUT1蛋白水平的增加，我们的数据显示UOK257细胞更倾向于糖酵解而不是脂质代谢（一种被称为“Warburg效应”的癌症现象）。UOK257细胞还具有较高的l-乳酸内流单羧酸转运蛋白1的表达水平，因此利用l-乳酸作为代谢燃料。由于它们对糖酵解的依赖性较高，我们能够通过2-脱氧葡萄糖处理选择性地抑制这些UOK257细胞的生长。这项工作表明，靶向糖酵解代谢可能用于治疗birt - hogg - dub<s:1>相关肾脏病变。
Under conditions of reduced tissue oxygenation, hypoxia-inducible factor (HIF) controls many processes, including angiogenesis and cellular metabolism, and also influences cell proliferation and survival decisions. HIF is centrally involved in tumour growth in inherited diseases that give rise to renal cell carcinoma (RCC), such as Von Hippel–Lindau syndrome and tuberous sclerosis complex. In this study, we examined whether HIF is involved in tumour formation of RCC in Birt–Hogg–Dubé syndrome. For this, we analysed a Birt–Hogg–Dubé patient-derived renal tumour cell line (UOK257) that is devoid of the Birt–Hogg–Dubé protein (BHD) and observed high levels of HIF activity. Knockdown of BHD expression also caused a threefold activation of HIF, which was not as a consequence of more HIF1α or HIF2α protein. Transcription of HIF target genes VEGF, BNIP3 and CCND1 was also increased. We found nuclear localization of HIF1α and increased expression of VEGF, BNIP3 and GLUT1 in a chromophobe carcinoma from a Birt–Hogg–Dubé patient. Our data also reveal that UOK257 cells have high lactate dehydrogenase, pyruvate kinase and 3-hydroxyacyl-CoA dehydrogenase activity. We observed increased expression of pyruvate dehydrogenase kinase 1 (a HIF gene target), which in turn leads to increased phosphorylation and inhibition of pyruvate dehydrogenase. Together with increased protein levels of GLUT1, our data reveal that UOK257 cells favour glycolytic rather than lipid metabolism (a cancer phenomenon termed the ‘Warburg effect’). UOK257 cells also possessed a higher expression level of the l-lactate influx monocarboxylate transporter 1 and consequently utilized l-lactate as a metabolic fuel. As a result of their higher dependency on glycolysis, we were able to selectively inhibit the growth of these UOK257 cells by treatment with 2-deoxyglucose. This work suggests that targeting glycolytic metabolism may be used therapeutically to treat Birt–Hogg–Dubé-associated renal lesions.
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影响因子：
8
作者：
Hartman, T. R.;Nicolas, E.;Klein-Szanto, A.;Al-Saleem, T.;Cash, T. P.;Simon, M. C.;Henske, E. P.
通讯作者：
Henske, E. P.
DOI：
10.1083/jcb.200403069
发表时间：
2004-07-19
期刊：
The Journal of cell biology
影响因子：
--
作者：
Harrington LS;Findlay GM;Gray A;Tolkacheva T;Wigfield S;Rebholz H;Barnett J;Leslie NR;Cheng S;Shepherd PR;Gout I;Downes CP;Lamb RF
通讯作者：
Lamb RF
影响因子：
4.7
作者：
Hemminki, K;Jiang, YW;Lindblad, P
通讯作者：
Lindblad, P
影响因子：
5.5
作者：
Deldicque, Louise;Theisen, Daniel;Francaux, Marc
通讯作者：
Francaux, Marc
DOI：
10.1073/pnas.91.14.6496
发表时间：
1994-07-05
影响因子：
11.1
作者：
FIRTH, JD;EBERT, BL;RATCLIFFE, PJ
通讯作者：
RATCLIFFE, PJ