Igf2 pathway dependency of the Trp53 developmental and tumour phenotypes.
Igf2 pathway dependency of the Trp53 developmental and tumour phenotypes.
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DOI：
10.1002/emmm.201101105
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发表时间：
2012-08
影响因子：
11.1
通讯作者：
Hassan, A. Bassim
中科院分区：
文献类型：
--
作者：
Haley, Victoria L.;Barnes, David J.;Sandovici, Ionel;Constancia, Miguel;Graham, Christopher F.;Pezzella, Francesco;Buehnemann, Claudia;Carter, Emma J.;Hassan, A. Bassim
胰岛素样生长因子2(IGF2)和转化相关蛋白53(TrP53)是发育和癌症过程中细胞生长和代谢的有效调节因子。体外证据表明，有几种机械途径相互作用。在此，我们测试了体内P53功能的丧失是否导致IGF2配体通路的依赖。在缺乏父亲表达的印记Igf2等位基因的p53纯合子缺失小鼠中，发生了发育死亡。出生后肺出血的进一步致死性仅发生在具有父亲Ig f2零等位基因的女性后代中，如果来自双杂合子零父亲，并且与特定的基因表达特征有关。有条件地缺失Igf2fl/fl可减弱p53fl/fl纯合缺失促进的快速肿瘤发病。在P53+/−双等位基因表达的女性中，加速的癌症和肉瘤的形成与P53的减少、杂合性丧失和细胞凋亡有关。IGF2在发育和肿瘤形成过程中对P53缺失表型的遗传依赖性表明，靶向IGF2途径在预防和治疗TrP53途径中断的人类肿瘤中可能是有用的。
Insulin-like growth factor 2 (IGF2) and the transformation related protein 53 (Trp53) are potent regulators of cell growth and metabolism in development and cancer. In vitro evidence suggests several mechanistic pathway interactions. Here, we tested whether loss of function of p53 leads to IGF2 ligand pathway dependency in vivo. Developmental lethality occurred in p53 homozygote null mice that lacked the paternal expressed allele of imprinted Igf2. Further lethality due to post-natal lung haemorrhage occurred in female progeny with Igf2 paternal null allele only if derived from double heterozygote null fathers, and was associated with a specific gene expression signature. Conditional deletion of Igf2fl/fl attenuated the rapid tumour onset promoted by homozygous deletion of p53fl/fl. Accelerated carcinoma and sarcoma tumour formation in p53+/− females with bi-allelic Igf2 expression was associated with reductions in p53 loss of heterozygosity and apoptosis. Igf2 genetic dependency of the p53 null phenotype during development and tumour formation suggests that targeting the IGF2 pathway may be useful in the prevention and treatment of human tumours with a disrupted Trp53 pathway.
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影响因子：
19
作者：
Feng Z;Levine AJ
通讯作者：
Levine AJ
影响因子：
64.5
作者：
Bond, GL;Hu, WW;Levine, AJ
通讯作者：
Levine, AJ
影响因子：
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作者：
BUCKBINDER, L;TALBOTT, R;KLEY, N
通讯作者：
KLEY, N