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Sustained activation of STAT5 is essential for chromatin remodeling and maintenance of mammary-specific function

¹ Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720
² Department of Chemical Engineering, Princeton University, Princeton, NJ 08544
³ California Pacific Medical Center Research Institute, San Francisco, CA 94107
⁴ Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892

Correspondence to Mina J. Bissell: MJBissell{at}lbl.gov; or Ren Xu: RXu{at}lbl.gov

Epithelial cells, once dissociated and placed in two-dimensional (2D) cultures, rapidly lose tissue-specific functions. We showed previously that in addition to prolactin, signaling by laminin-111 was necessary to restore functional differentiation of mammary epithelia. Here, we elucidate two additional aspects of laminin-111 action. We show that in 2D cultures, the prolactin receptor is basolaterally localized and physically segregated from its apically placed ligand. Detachment of the cells exposes the receptor to ligation by prolactin leading to signal transducers and activators of transcription protein 5 (STAT5) activation, but only transiently and not sufficiently for induction of milk protein expression. We show that laminin-111 reorganizes mammary cells into polarized acini, allowing both the exposure of the prolactin receptor and sustained activation of STAT5. The use of constitutively active STAT5 constructs showed that the latter is necessary and sufficient for chromatin reorganization and β-casein transcription. These results underscore the crucial role of continuous laminin signaling and polarized tissue architecture in maintenance of transcription factor activation, chromatin organization, and tissue-specific gene expression.

© 2009 Xu et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jcb.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

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This article has been cited by other articles:

• Sedwick, C. (2009). It takes two to party with chromatin. JCB 184: 2-2 [Full Text]  
• Short, B. (2009). Mina Bissell: Context is everything. JCB 185: 374-375 [Full Text]  

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