A HIF-LIMD1 negative feedback mechanism mitigates the pro-tumorigenic effects of hypoxia.
A HIF-LIMD1 negative feedback mechanism mitigates the pro-tumorigenic effects of hypoxia.
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DOI：
10.15252/emmm.201708304
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发表时间：
2018-08
影响因子：
11.1
通讯作者：
Sharp TV
中科院分区：
文献类型：
--
作者：
Foxler DE;Bridge KS;Foster JG;Grevitt P;Curry S;Shah KM;Davidson KM;Nagano A;Gadaleta E;Rhys HI;Kennedy PT;Hermida MA;Chang TY;Shaw PE;Reynolds LE;McKay TR;Wang HW;Ribeiro PS;Plevin MJ;Lagos D;Lemoine NR;Rajan P;Graham TA;Chelala C;Hodivala-Dilke KM;Spendlove I;Sharp TV
低氧诱导因子（HIF）是由HIF-α和HIF-β亚基组成的异源二聚体转录因子家族。HIF表达延长是细胞转化、肿瘤发生和转移的关键因素。因此，缺氧条件下的HIF降解是一种重要的稳态和肿瘤抑制机制。LIMD 1在生理氧水平（常氧）下与PHD 2和VHL复合，以促进HIF-α亚基的蛋白酶体降解。在这里，我们将LIMD 1确定为HIF-1靶基因，其通过调节PHD 2-LIMD 1-VHL复合物的形成来介导低氧HIF-α降解的先前未表征的负调节反馈机制。LIMD 1表达的低氧诱导导致HIF-α蛋白降解增加，抑制HIF-1靶基因表达、肿瘤生长和血管形成。此外，我们报告说，LIMD 1基因座的拷贝数变异发生在47.1%的肺腺癌患者中，与HIF靶基因签名的表达增强相关，是一个负面的预后指标。总之，我们的数据为LIMD 1阴性肺癌的病因学、诊断和预后开辟了新的研究领域。
The adaptive cellular response to low oxygen tensions is mediated by the hypoxia‐inducible factors (HIFs), a family of heterodimeric transcription factors composed of HIF‐α and HIF‐β subunits. Prolonged HIF expression is a key contributor to cellular transformation, tumorigenesis and metastasis. As such, HIF degradation under hypoxic conditions is an essential homeostatic and tumour‐suppressive mechanism. LIMD1 complexes with PHD2 and VHL in physiological oxygen levels (normoxia) to facilitate proteasomal degradation of the HIF‐α subunit. Here, we identify LIMD1 as a HIF‐1 target gene, which mediates a previously uncharacterised, negative regulatory feedback mechanism for hypoxic HIF‐α degradation by modulating PHD2‐LIMD1‐VHL complex formation. Hypoxic induction of LIMD1 expression results in increased HIF‐α protein degradation, inhibiting HIF‐1 target gene expression, tumour growth and vascularisation. Furthermore, we report that copy number variation at the LIMD1 locus occurs in 47.1% of lung adenocarcinoma patients, correlates with enhanced expression of a HIF target gene signature and is a negative prognostic indicator. Taken together, our data open a new field of research into the aetiology, diagnosis and prognosis of LIMD1‐negative lung cancers.
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DOI：
10.1016/j.cub.2010.02.035
发表时间：
2010-04-13
期刊：
Current biology : CB
影响因子：
--
作者：
Das Thakur M;Feng Y;Jagannathan R;Seppa MJ;Skeath JB;Longmore GD
通讯作者：
Longmore GD
影响因子：
14.9
作者：
Colaprico A;Silva TC;Olsen C;Garofano L;Cava C;Garolini D;Sabedot TS;Malta TM;Pagnotta SM;Castiglioni I;Ceccarelli M;Bontempi G;Noushmehr H
通讯作者：
Noushmehr H
影响因子：
16.6
作者：
Goodwin J;Neugent ML;Lee SY;Choe JH;Choi H;Jenkins DMR;Ruthenborg RJ;Robinson MW;Jeong JY;Wake M;Abe H;Takeda N;Endo H;Inoue M;Xuan Z;Yoo H;Chen M;Ahn JM;Minna JD;Helke KL;Singh PK;Shackelford DB;Kim JW
通讯作者：
Kim JW
影响因子：
9.2
作者：
Codelia, Veronica A.;Sun, Gongping;Irvine, Kenneth D.
通讯作者：
Irvine, Kenneth D.
影响因子：
4.8
作者：
Gorospe M;Tominaga K;Wu X;Fähling M;Ivan M
通讯作者：
Ivan M