Depletion of nuclear actin is a key mediator of quiescence in epithelial cells

被引:91
作者
Spencer, Virginia A. [1 ]
Costes, Sylvain [1 ]
Inman, Jamie L. [1 ]
Xu, Ren [1 ]
Chen, James [1 ]
Hendzel, Michael J. [2 ,3 ]
Bissell, Mina J. [1 ]
机构
[1] Univ Calif Berkeley, Lawrence Berkeley Lab, Div Life Sci, Berkeley, CA 94720 USA
[2] Univ Alberta, Dept Oncol, Edmonton, AB T6G 1Z2, Canada
[3] Cross Canc Inst, Edmonton, AB T6G 1Z2, Canada
基金
加拿大健康研究院;
关键词
Actin; Laminin; Microenvironment; Nucleus; RNA-POLYMERASE-II; EXTRACELLULAR-MATRIX; HUMAN-BREAST; BASEMENT-MEMBRANE; GENE-EXPRESSION; BRANCHING MORPHOGENESIS; MAMMARY-GLAND; FUNCTIONAL-DIFFERENTIATION; TRANSCRIPTION FACTORS; HISTONE ACETYLATION;
D O I
10.1242/jcs.073197
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Functional differentiation is orchestrated by precise growth-regulatory controls conveyed by the tissue microenvironment. Cues from laminin 111 (LN1) lower transcription and suppress mammary epithelial cell growth in culture, but how LN1 induces quiescence is unknown. Recent literature points to involvement of nuclear beta-actin in transcriptional regulation. Here, we show that quiescence induced by growth factor withdrawal, or LN1 addition, rapidly decreases nuclear beta-actin. LN1, but not other extracellular matrix (ECM) molecules, decreases the levels of nuclear beta-actin and destabilizes RNA polymerase (RNA Pol) II and III binding to transcription sites, leading to a dramatic drop in transcription and DNA synthesis. Constitutive overexpression of globular beta-actin in the nucleus reverses the effect of LN1 on transcription and RNA Pol II association and prevents the cells from becoming quiescent in the presence of LN1. The physiological relevance of our findings was verified by identifying a clear spatial separation of LN1 and beta-actin in developing mammary end buds. These data indicate a novel role for nuclear beta-actin in growth arrest of epithelial cells and underscore the importance of the integrity of the basement membrane in homeostasis.
引用
收藏
页码:123 / 132
页数:10
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