Targeted inactivation of the p21(WAF1/cip1) gene enhances Apc-initiated tumor formation and the tumor-promoting activity of a Western-style high-risk diet by altering cell maturation in the intestinal mucosal.
Targeted inactivation of the p21(WAF1/cip1) gene enhances Apc-initiated tumor formation and the tumor-promoting activity of a Western-style high-risk diet by altering cell maturation in the intestinal mucosal.
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发表时间：
2001
期刊：
影响因子：
11.2
通讯作者：
W. Yang;J. Mathew;A. Velcich;W. Edelmann;R. Kucherlapati;M. Lipkin;K. Yang;L. Augenlicht
中科院分区：
文献类型：
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作者：
W. Yang;J. Mathew;A. Velcich;W. Edelmann;R. Kucherlapati;M. Lipkin;K. Yang;L. Augenlicht
消除编码细胞周期蛋白激酶抑制剂p21（WAF 1/cip1）的基因的两个等位基因会增加Apc 1638 +/-小鼠肠道肿瘤的发生频率和大小，这些小鼠遗传了Apc基因的突变等位基因，如果单个p21等位基因失活，则会观察到中间效应。肿瘤形成的增加与p21缺陷小鼠肠粘膜中细胞成熟的改变有关--细胞增殖增加，凋亡减少，杯状细胞分化--这也是p21基因剂量的函数。此外，模仿结肠癌主要风险因素（高脂肪和磷酸盐，低钙和维生素D）的西式饮食加速了Apc1638 +/-小鼠的肿瘤形成，并且单个或两个p21等位基因的丢失与这种饮食的肿瘤促进作用相加，导致更多和更大的肿瘤，以及生存时间的高度显着减少。因此，p21通常抑制APC启动的肿瘤形成，并且在这方面是单倍不足的。这与最近的报道一致，即Apc通过改变β-连环蛋白-Tcf信号传导上调c-myc表达来启动肿瘤形成，然后c-myc上调cdk 4，cdk 4的活性被p21抑制。p21表达降低也是患者预后不良的标志，所提供的数据表明，结肠癌治疗患者的饮食改变可能对改善预后非常有效。
Elimination of both alleles of the gene that encodes the cyclin kinase inhibitor p21(WAF1/cip1) increases the frequency and size of intestinal tumors in Apc1638+/- mice that inherit a mutant allele of the Apc gene, and intermediate effects are seen if a single p21 allele is inactivated. The increased tumor formation is associated with altered cell maturation in the intestinal mucosa of the p21-deficient mice--increased cell proliferation, and decreased apoptosis, and goblet cell differentiation--that is also a function of p21 gene dosage. Moreover, a Western-style diet that mimics principal risk factors for colon cancer (high fat and phosphate, low calcium and vitamin D) accelerates tumor formation in Apc1638+/- mice, and the loss of a single or both p21 alleles is additive with the tumor-promoting effects of this diet, resulting in more and larger tumors, and a highly significant decrease in survival time. Thus, p21 normally suppresses Apc-initiated tumor formation and is haplo-insufficient in this regard. This is consistent with recent reports that Apc initiates tumor formation by up-regulating c-myc expression through altered beta-catenin-Tcf signaling and that c-myc then up-regulates cdk4, whose activity is inhibited by p21. Decreased expression of p21 is also a marker of poor prognosis in patients, and the data presented suggest that dietary alterations in patients undergoing treatment for colon cancer might be highly effective in improving outcome.