Tissue phenotype depends on reciprocal interactions between the extracellular matrix and the structural organization of the nucleus.

TitleTissue phenotype depends on reciprocal interactions between the extracellular matrix and the structural organization of the nucleus.
Publication TypeJournal Article
Year of Publication1998
AuthorsLelièvre SA, Weaver VM, Nickerson JA, Larabell CA, Bhaumik A, Petersen OW, Bissell MJ
JournalProc Natl Acad Sci U S A
Volume95
Issue25
Pagination14711-6
Date Published1998 Dec 8
ISSN0027-8424
KeywordsCell Nucleus, Extracellular Matrix, Extracellular Matrix Proteins, Female, Gene Expression Regulation, Humans, Morphogenesis, Nuclear Proteins, Tumor Cells, Cultured
Abstract

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.

Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID9843954
PubMed Central IDPMC24514
Grant ListCA-64786 / CA / NCI NIH HHS / United States