LKB1 preserves genome integrity by stimulating BRCA1 expression.
LKB1 preserves genome integrity by stimulating BRCA1 expression.
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DOI：
10.1093/nar/gku1294
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发表时间：
2015-01
影响因子：
14.9
通讯作者：
Wajapeyee N
中科院分区：
文献类型：
--
作者：
Gupta R;Liu AY;Glazer PM;Wajapeyee N
丝氨酸/苏氨酸激酶11（STK 11，也称为LKB 1）在许多人类癌症中起肿瘤抑制剂的作用。然而，自相矛盾的是，小鼠胚胎成纤维细胞LKB 1的缺失导致对癌基因诱导的转化的抗性。因此，目前尚不清楚为什么LKB 1的缺失会导致发生各种癌症的易感性增加。在这里，我们表明LKB 1保护细胞免受遗传毒性应激。与表达LKB 1的细胞相比，缺乏LKB 1的细胞显示出对辐射的敏感性增加，积累更多的DNA双链断裂，显示出有缺陷的同源定向DNA修复（HDR），并显示出增加的突变率。相反，LKB 1在缺乏LKB 1的细胞中的异位表达保护它们免受遗传毒性应激诱导的DNA损伤，并防止突变的积累。我们发现，LKB 1转录后刺激HDR基因BRCA 1的表达，抑制RNA结合蛋白，HU抗原R的细胞质定位，在AMP激酶依赖的方式和稳定BRCA 1 mRNA。缺乏BRCA 1的细胞与缺乏LKB 1的细胞相似，显示出增加的基因组不稳定性，BRCA 1的异位表达挽救了LKB 1缺失诱导的对遗传毒性应激的敏感性。总的来说，我们的研究结果表明，LKB 1是基因组完整性的关键调节因子，并揭示了LKB 1介导的肿瘤抑制的新机制，对癌症预防具有直接的治疗意义。
Serine/threonine kinase 11 (STK11, also known as LKB1) functions as a tumor suppressor in many human cancers. However, paradoxically loss of LKB1 in mouse embryonic fibroblast results in resistance to oncogene-induced transformation. Therefore, it is unclear why loss of LKB1 leads to increased predisposition to develop a wide variety of cancers. Here, we show that LKB1 protects cells from genotoxic stress. Cells lacking LKB1 display increased sensitivity to irradiation, accumulates more DNA double-strand breaks, display defective homology-directed DNA repair (HDR) and exhibit increased mutation rate, compared with that of LKB1-expressing cells. Conversely, the ectopic expression of LKB1 in cells lacking LKB1 protects them against genotoxic stress-induced DNA damage and prevents the accumulation of mutations. We find that LKB1 post-transcriptionally stimulates HDR gene BRCA1 expression by inhibiting the cytoplasmic localization of the RNA-binding protein, HU antigen R, in an AMP kinase-dependent manner and stabilizes BRCA1 mRNA. Cells lacking BRCA1 similar to the cell lacking LKB1 display increased genomic instability and ectopic expression of BRCA1 rescues LKB1 loss-induced sensitivity to genotoxic stress. Collectively, our results demonstrate that LKB1 is a crucial regulator of genome integrity and reveal a novel mechanism for LKB1-mediated tumor suppression with direct therapeutic implications for cancer prevention.
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影响因子：
--
作者：
Hawley SA;Boudeau J;Reid JL;Mustard KJ;Udd L;Mäkelä TP;Alessi DR;Hardie DG
通讯作者：
Hardie DG
影响因子：
29.4
作者：
Martinez-Chantar, Maria L.;Vazquez-Chantada, Mercedes;Mato, Jose M.
通讯作者：
Mato, Jose M.
影响因子：
11.2
作者：
Lal S;Burkhart RA;Beeharry N;Bhattacharjee V;Londin ER;Cozzitorto JA;Romeo C;Jimbo M;Norris ZA;Yeo CJ;Sawicki JA;Winter JM;Rigoutsos I;Yen TJ;Brody JR
通讯作者：
Brody JR
影响因子：
64.8
作者：
Lowe, SW;Cepero, E;Evan, G
通讯作者：
Evan, G
DOI：
10.1073/pnas.122254599
发表时间：
2002-06-25
影响因子：
11.1
作者：
Jishage, K;Nezu, J;Suzuki, H
通讯作者：
Suzuki, H