Jnk2 effects on tumor development, genetic instability and replicative stress in an oncogene-driven mouse mammary tumor model.
Jnk2 effects on tumor development, genetic instability and replicative stress in an oncogene-driven mouse mammary tumor model.
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DOI：
10.1371/journal.pone.0010443
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发表时间：
2010-05-03
期刊：
影响因子：
3.7
通讯作者：
Van Den Berg CL
中科院分区：
文献类型：
--
作者：
Chen P;O'Neal JF;Ebelt ND;Cantrell MA;Mitra S;Nasrazadani A;Vandenbroek TL;Heasley LE;Van Den Berg CL
癌基因诱导细胞增殖，导致复制应激、DNA损伤和基因组不稳定。多种细胞应激可激活c-Jun n -末端激酶（JNK）蛋白，但很少有研究直接探讨JNK亚型在肿瘤发展中的作用。本研究表明，与jnk2野生型小鼠相比，表达多瘤中间T抗原转基因的jnk2敲除小鼠发生乳腺肿瘤的时间更早，肿瘤多样性更高。缺乏jnk2的表达与较高的肿瘤非整倍体和降低的DNA损伤反应相关，其标志是较少的pH2AX和53BP1核灶。比较基因组杂交进一步证实了PyV MT/jnk2−/−肿瘤的基因组不稳定性增加。在体外，PyV MT/jnk2−/−细胞经历了复制应激和细胞死亡，这证明了BrdU掺入降低，染色质许可和DNA复制因子1 （CDT1）和p21Waf1蛋白表达持续，血清刺激后Chk1磷酸化，但这种反应与p53 Ser15磷酸化无关。腺病毒过表达CDT1导致jnk2野生型和敲除细胞之间存在类似的差异。在经受紫外线诱导的单链DNA断裂的正常乳腺细胞中，JNK2定位于RPA（复制蛋白A）包被的链上，这表明JNK2对单链DNA损伤的早期反应，对随后的DNA修复蛋白募集至关重要。总之，这些数据支持JNK2通过协调细胞周期进程和DNA损伤修复机制来防止复制应激。
Oncogenes induce cell proliferation leading to replicative stress, DNA damage and genomic instability. A wide variety of cellular stresses activate c-Jun N-terminal kinase (JNK) proteins, but few studies have directly addressed the roles of JNK isoforms in tumor development. Herein, we show that jnk2 knockout mice expressing the Polyoma Middle T Antigen transgene developed mammary tumors earlier and experienced higher tumor multiplicity compared to jnk2 wildtype mice. Lack of jnk2 expression was associated with higher tumor aneuploidy and reduced DNA damage response, as marked by fewer pH2AX and 53BP1 nuclear foci. Comparative genomic hybridization further confirmed increased genomic instability in PyV MT/jnk2−/− tumors. In vitro, PyV MT/jnk2−/− cells underwent replicative stress and cell death as evidenced by lower BrdU incorporation, and sustained chromatin licensing and DNA replication factor 1 (CDT1) and p21Waf1 protein expression, and phosphorylation of Chk1 after serum stimulation, but this response was not associated with phosphorylation of p53 Ser15. Adenoviral overexpression of CDT1 led to similar differences between jnk2 wildtype and knockout cells. In normal mammary cells undergoing UV induced single stranded DNA breaks, JNK2 localized to RPA (Replication Protein A) coated strands indicating that JNK2 responds early to single stranded DNA damage and is critical for subsequent recruitment of DNA repair proteins. Together, these data support that JNK2 prevents replicative stress by coordinating cell cycle progression and DNA damage repair mechanisms.
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影响因子：
15.9
作者：
Bosco, Emily E.;Wang, Ying;Knudsen, Erik S.
通讯作者：
Knudsen, Erik S.
DOI：
10.1083/jcb.200704138
发表时间：
2007-11-19
期刊：
The Journal of cell biology
影响因子：
--
作者：
Liu E;Lee AY;Chiba T;Olson E;Sun P;Wu X
通讯作者：
Wu X
影响因子：
4.3
作者：
Fernandez-Capetillo, Oscar;Celeste, Arkady;Nussenzweig, Andre
通讯作者：
Nussenzweig, Andre
影响因子：
6
作者：
Lin, EY;Jones, JG;Pollard, JW
通讯作者：
Pollard, JW
DOI：
10.1038/nrc2657
发表时间：
2009-06
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
通讯作者：
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