Suppression of apoptosis by basement membrane requires three-dimensional tissue organization and withdrawal from the cell cycle
Suppression of apoptosis by basement membrane requires three-dimensional tissue organization and withdrawal from the cell cycle
复制标题
DOI：
10.1073/pnas.93.8.3509
复制
发表时间：
1996-04-16
影响因子：
11.1
通讯作者：
Bissell, MJ
中科院分区：
文献类型：
--
作者：
Boudreau, N;Werb, Z;Bissell, MJ
基底膜（BM）细胞外基质诱导乳腺上皮细胞分化并抑制细胞凋亡，而缺乏BM的细胞失去其分化表型并经历细胞凋亡。已知诱导β-酪蛋白表达的纯化BM组分的添加并不能防止细胞凋亡，表明更复杂的BM是必要的。细胞凋亡发生或不发生的培养条件的比较使我们能够将细胞凋亡的抑制与细胞周期的完全退出联系起来，这仅在细胞响应BM获得三维肺泡结构时观察到。在没有这种形态的情况下，细胞周期蛋白激酶抑制剂p21/WAF-1和c-myc、cyclin D1等增殖信号均表达，视网膜母细胞瘤蛋白（Rb）当我们在静止期细胞中过表达c-myc或在细胞仍在循环时过表达p21时，诱导凋亡。在缺乏三维肺泡结构的情况下，乳腺上皮细胞分泌许多因子，包括转化生长因子α和腱生蛋白，当将其外源性添加到静止细胞中时，诱导c-myc和白细胞介素-β 1-转化酶（ICE）mRNA的表达并导致凋亡。这些实验表明，正确的组织结构对于长期稳态、抑制凋亡、和维持分化的表型。
The basement membrane (BM) extracellular matrix induces differentiation and suppresses apoptosis in mammary epithelial cells, whereas cells lacking BM lose their differentiated phenotype and undergo apoptosis, Addition of purified BM components, which are known to induce beta-casein expression, did not prevent apoptosis, indicating that a more complex BM was necessary. A comparison of culture conditions where apoptosis would or would not occur allowed us to relate inhibition of apoptosis to a complete withdrawal from the cell cycle, which was observed only when cells acquired a three-dimensional alveolar structure in response to BM, In the absence of this morphology, both the G(1) cyclin kinase inhibitor p21/WAF-1 and positive proliferative signals including c-myc and cyclin D1 were expressed and the retinoblastoma protein (Rb) continued to be hyperphosphorylated, When we overexpressed either c-myc in quiescent cells or p21 when cells were still cycling, apoptosis was induced. In the absence of three-dimensional alveolar structures, mammary epithelial cells secrete a number of factors including transforming growth factor alpha and tenascin, which when added exogenously to quiescent cells induced expression of c-myc and interleukin-beta 1-converting enzyme (ICE) mRNA and led to apoptosis, These experiments demonstrate that a correct tissue architecture is crucial for long-range homeostasis, suppression of apoptosis, and maintenance of differentiated phenotype.