gamma-ray-induced apoptosis in transgenic mice with proliferative abnormalities in their intestinal epithelium: Re-entry of villus enterocytes into the cell cycle does not affect their radioresistance but enhances the radiosensitivity of the crypt by inducing p53
gamma-ray-induced apoptosis in transgenic mice with proliferative abnormalities in their intestinal epithelium: Re-entry of villus enterocytes into the cell cycle does not affect their radioresistance but enhances the radiosensitivity of the crypt by inducing p53
复制标题
DOI：
10.1038/sj.onc.1201176
复制
发表时间：
1997-07-10
期刊：
影响因子：
8
通讯作者：
Gordon, JI
中科院分区：
文献类型：
--
作者：
Coopersmith, CM;Gordon, JI
增殖的隐窝上皮细胞的放射敏感性使得肠道成为使用放射疗法治疗腹部癌症的主要限制因素。当有丝分裂后的上皮细胞从小鼠小肠隐窝迁移到相邻绒毛的基部时，它们迅速失去响应于电离辐射（IR）而经历凋亡的能力。为了确定这种放射抗性是否反映了从细胞周期中退出，我们使用谱系特异性启动子来指导野生型猿猴病毒40 T抗原的表达，在FVB/N转基因小鼠中，SV 40 TAgWt诱导的pRB依赖性重新进入细胞周期与6戈伊或12戈伊γ射线照射后4小时或24小时获得IR刺激的细胞凋亡无关，SV 40 TAgWt和K-ras（Val 12）的共表达在周期性绒毛肠上皮细胞中产生发育异常，但对IR没有向凋亡反应性转变。这些发现表明绒毛肠上皮细胞的放射抗性不仅仅是由于它们的细胞周期停滞，并且可能是它们的微环境的反映。绒毛肠上皮细胞重新进入细胞周期增加了隐窝上皮的放射敏感性，而不改变Bcl-2、Bcl-x（L）、巴克或Bar表达。这种作用仅在IR后显现，并且基于用突变型SV 40 TAG获得的结果，依赖于达到绒毛肠上皮细胞增殖的临界水平。与正常隐窝对IR的反应一样，IR刺激的隐窝凋亡的绒毛来源的增强与p53和Raf-l的诱导有关，并且依赖于p53。与正常隐窝对IR的反应不同，p53诱导涉及分布在整个隐窝中的细胞并且凋亡反应不限于隐窝的下半部分，这些结果表明，由循环肠上皮细胞启动的信号可以传递到隐窝上皮细胞，诱导p53和影响其IR诱导的凋亡，了解潜在的信号通路可能提供有关如何修改正常隐窝的放射敏感性的治疗效益的线索。
The radiosensitivity of proliferating crypt epithelial cells makes the gut a major limiting factor in the use of radiotherapy for treatment of abdominal cancers, As post-mitotic epithelial cells migrate from mouse small intestinal crypts to the base of adjacent villi, they rapidly lose their ability to undergo apoptosis in response to ionizing irradiation (IR), To determine whether this radioresistance reflects withdrawal from the cell cycle, we used a lineage-specific promoter to direct expression of wild type Simian virus 40 T antigen (SV40 TAgWt) to villus, but not crypt, enterocytes in FVB/N transgenic mice, SV40 TAgWt induced, pRB-dependent, re-entry into the cell cycle is not associated with the acquisition of IR-stimulated apoptosis 4 h or 24 h after 6 Gy or 12 Gy of gamma-irradiation, Coexpression of SV40 TAgWt and K-ras(Val12) produces dysplasia in cycling villus enterocytes but no shift towards apoptotic responsiveness to IR, These findings suggest that the radioresistance of villus enterocytes is not simply due to their cell cycle arrest and may be a reflection of their microenvironment, Remarkably, reentry of villus enterocytes to the cell cycle increases the radiosensitivity of the crypt epithelium without changing Bcl-2, Bcl-x(L), Bak, or Bar expression, This effect is only manifest after IR and, based upon results obtained with mutant SV40 TAgs, depends upon reaching a critical level of proliferation in villus enterocytes, Like the normal crypt response to IR, the villus-derived enhancement of IR-stimulated crypt apoptosis is associated with an induction of p53 and Raf-l, and is dependent upon p53, Unlike the normal crypt response to IR, the p53 induction involves cells distributed throughout the crypt and the apoptotic response is not confined to the lower half of the crypt, These results indicate that signals initiated by cycling enterocytes can be transmitted to the crypt epithelium to induce p53 and influence their IR-induced apoptosis, Understanding the underlying signaling pathways may provide clues about how to modify a normal crypt's radiosensitivity for therapeutic benefit.