Inactivation of the p19(ARF) tumor suppressor affects intestinal epithelial cell proliferation and integrity.
Inactivation of the p19(ARF) tumor suppressor affects intestinal epithelial cell proliferation and integrity.
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DOI：
10.1002/jcb.21779
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发表时间：
2008-08-15
影响因子：
4
通讯作者：
Hiebert, Scott W.
中科院分区：
文献类型：
--
作者：
Farmer, Tiffany E.;Williams, Christopher S.;Washington, M. Kay;Hiebert, Scott W.
p19ARF是一种肿瘤抑制因子，在人类癌症中经常缺失。它位于染色体9p21，与p16ink4a共享外显子2和3，p16ink4a也被这些癌症相关缺失灭活。p19 ARF被认为通过激活p53肿瘤抑制因子抑制肿瘤发生的“经典途径”。作为对过度增殖信号（如癌基因表达）的响应，p19 ARF被诱导并与MDM 2泛素连接酶结合，将其隔离在核仁中以允许p53积累。然而，p19ARF也具有MDM2和p53独立的功能。在人类结肠癌中，p19ARF很少被删除，但它更经常被DNA启动子甲基化沉默。在这里，我们表明，在小鼠中的p19ARF的失活增加结肠上皮的隐窝中的循环细胞的数量。此外，p19ARF的失活加剧了葡聚糖硫酸钠（DSS）引起的结肠上皮溃疡。这些效应与在缺乏骨髓易位基因相关1（Mtgr 1）的小鼠中观察到的效应相似，缺乏这两种基因的小鼠对DSS表现出更大的敏感性。令人惊讶的是，失活的p19ARF恢复Mtgr 1缺陷小鼠的分泌谱系的损失，这表明p19ARF在小肠上皮细胞中的额外作用。
p19ARF is a tumor suppressor that is frequently deleted in human cancer. It lies at chromosome 9p21 and shares exons 2 and 3 with p16ink4a, which is also inactivated by these cancer-associated deletions. The “canonical pathway” by which p19ARF is thought to suppress tumorigenesis through activation of the p53 tumor suppressor. In response to hyperproliferative signals, such as expression of oncogenes, p19ARF is induced and binds to the MDM2 ubiquitin ligase, sequestering it in the nucleolus to allow the accumulation of p53. However, p19ARF also has MDM2 and p53 independent functions. In human colon cancer, p19ARF is only rarely deleted, but it is more frequently silenced by DNA promoter methylation. Here we show that inactivation of p19ARF in mice increases the number of cycling cells in the crypts of the colonic epithelium. Moreover, inactivation of p19ARF exacerbated the ulceration of the colonic epithelium caused by dextran sodium sulfate (DSS). These effects were similar to those observed in mice lacking myeloid translocation gene-related-1 (Mtgr1), and mice lacking both of these genes showed an even greater sensitivity to DSS. Surprisingly, inactivation of p19ARF restored the loss of the secretory lineage in mice deficient in Mtgr1, suggesting an additional role for p19ARF in the small intestinal epithelium.
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影响因子：
5.3
作者：
Moore, Amy C.;Amann, Joseph M.;Hiebert, Scott W.
通讯作者：
Hiebert, Scott W.
影响因子：
5.3
作者：
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64.8
作者：
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影响因子：
5
作者：
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作者：
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通讯作者：
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