Tissue phenotype depends on reciprocal interactions between the extracellular matrix and the structural organization of the nucleus
Tissue phenotype depends on reciprocal interactions between the extracellular matrix and the structural organization of the nucleus
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DOI：
10.1073/pnas.95.25.14711
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发表时间：
1998-12-08
影响因子：
11.1
通讯作者：
Bissell, MJ
中科院分区：
文献类型：
--
作者：
Lelièvre, SA;Weaver, VM;Bissell, MJ
是什么决定了细胞内的核组织，以及这种组织本身是否可以在组织内施加细胞功能仍然是未知的。为了探讨核组织与组织结构和功能之间的关系，我们使用了人乳腺上皮细胞腺泡形态发生的模型。当在重构基底膜（rBM）内培养时，HMT-3522细胞形成极化和生长停滞的组织样腺泡，具有中央腔并存款内源性BM。我们发现，rBM诱导的形态伴随着核基质蛋白NuMA，剪接因子SRm 160和细胞周期调节Rb的重新定位。这些蛋白质有不同的分布模式，具体的增殖，生长停滞，腺泡形成，而核纤层蛋白，核纤层蛋白B的分布，保持不变。NuMA重新定位到病灶，随着形态发生的进展，这些病灶合并成更大的集合体。干扰组蛋白乙酰化的腺泡中的阿伐他汀A治疗改变染色质结构，破坏NuMA焦点，并诱导细胞增殖。此外，用NuMA抗体处理瞬时透化的腺泡导致NuMA病灶的破坏、组蛋白乙酰化的改变、金属蛋白酶的活化和内源性BM的分解。这些结果实验证明了细胞外基质，核组织和组织表型之间的动态相互作用。他们进一步表明，核组织本身可以调节细胞和组织表型，而不是被动地反映基因表达的变化。
What determines the nuclear organization within a cell and whether this organization itself can impose cellular function within a tissue remains unknown. To explore the relationship between nuclear organization and tissue architecture and function, we used a model of human mammary epithelial cell acinar morphogenesis. When cultured within a reconstituted basement membrane (rBM), HMT-3522 cells form polarized and growth-arrested tissue-like acini with a central lumen and deposit an endogenous BM. We show that rBM-induced morphogenesis is accompanied by relocalization of the nuclear matrix proteins NuMA, splicing factor SRm160, and cell cycle regulator Rb. These proteins had distinct distribution patterns specific for proliferation, growth arrest, and acini formation, whereas the distribution of the nuclear lamina protein, lamin B, remained unchanged. NuMA relocalized to foci, which coalesced into larger assemblies as morphogenesis progressed. Perturbation of histone acetylation in the acini by trichostatin A treatment altered chromatin structure, disrupted NuMA foci, and induced cell proliferation. Moreover, treatment of transiently permeabilized acini with a NuMA antibody led to the disruption of NuMA foci, alteration of histone acetylation, activation of metalloproteases, and breakdown of the endogenous BM. These results experimentally demonstrate a dynamic interaction between the extracellular matrix, nuclear organization, and tissue phenotype. They further show that rather than passively reflecting changes in gene expression, nuclear organization itself can modulate the cellular and tissue phenotype.