PRAK suppresses oncogenic ras-induced hematopoietic cancer development by antagonizing the JNK pathway.
PRAK suppresses oncogenic ras-induced hematopoietic cancer development by antagonizing the JNK pathway.
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DOI：
10.1158/1541-7786.mcr-11-0576
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发表时间：
2012-06
期刊：
影响因子：
--
通讯作者：
Sun P
中科院分区：
文献类型：
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作者：
Yoshizuka N;Lai M;Liao R;Cook R;Xiao C;Han J;Sun P
p38 MAPK通路调节多种生理和病理过程，包括癌症的发展。PRAK是一种p38底物蛋白激酶，以前曾参与抑制皮肤癌的发生。在目前的研究中，我们证明PRAK缺失加速了小鼠模型中造血系统癌症的发展，该小鼠模型含有致癌ras等位基因Eμ-N-RasG 12 D，在造血细胞中特异性表达。进一步的研究表明，PRAK缺乏增强造血肿瘤发生与体内和从脾分离的原代造血细胞中JNK通路的过度活化有关。在原代脾细胞中，PRAK缺陷进一步增强致癌ras诱导的细胞增殖，并以JNK依赖的方式促进ras介导的半固体培养基上的集落形成。此外，PRAK的缺失导致ras诱导的衰老标志物积累的消除。这些发现表明PRAK通过拮抗致癌ras诱导的JNK通路的激活来抑制该小鼠模型中的造血癌形成。我们的研究结果表明，PRAK可能在多种类型的癌症中起肿瘤抑制剂的作用。
The p38 MAPK pathway regulates multiple physiological and pathological processes, including cancer development. PRAK, a p38 substrate protein kinase, has previously been implicated in the suppression of skin carcinogenesis. In the current study, we demonstrate that PRAK deletion accelerates hematopoietic cancer development in a mouse model harboring an oncogenic ras allele, Eμ-N-RasG12D, specifically expressed in hematopoietic cells. Further investigation reveals that enhanced hematopoietic tumorigenesis by PRAK deficiency is associated with hyper-activation of the JNK pathway both in vivo and in primary hematopoietic cells isolated from spleens. In primary splenocytes, PRAK deficiency further enhanced oncogenic ras-induced cell proliferation, and promoted ras-mediated colony formation on semi-solid medium in a JNK-dependent manner. In addition, deletion of PRAK leads to abrogation of ras-induced accumulation of senescence markers. These findings indicate that PRAK suppresses hematopoietic cancer formation in this mouse model by antagonizing oncogenic ras-induced activation of the JNK pathway. Our results suggest that PRAK may function as a tumor suppressor in multiple types of cancers.