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First published online 1 March 2005
doi: 10.1242/jcs.01709

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Higher-order nuclear organization in growth arrest of human mammary epithelial cells: a novel role for telomere-associated protein TIN2

¹ Buck Institute for Age Research, 8001 Redwood Boulevard, Novato, California 94945, USA
² Department of Basic Medical Sciences and Cancer Center, Purdue University, 625 Harrison Street, West Lafayette, Indiana 47907-2026, USA
³ Life Sciences Division, Lawrence Berkeley National Laboratory, 1 Cyclotron Road, Berkeley, California, 94720, USA
⁴ Structural Cell Biology Unit, The Panum Institute, University of Copenhagen, Blegdamsvej 3, DK-2200, Copenhagen, Denmark.

^* Author for correspondence (e-mail: lelievre{at}purdue.edu)

Accepted 6 January 2005

Nuclear organization, such as the formation of specific nuclear subdomains, is generally thought to be involved in the control of cellular phenotype; however, there are relatively few specific examples of how mammalian nuclei organize during radical changes in phenotype, such as those occurring during differentiation and growth arrest. Using human mammary epithelial cells in which growth arrest is essential for morphological differentiation, we show that the arrest of cell proliferation is accompanied by a reorganization of the telomere-associated protein, TIN2, into one to three large nuclear subdomains. The large TIN2 domains do not contain telomeres and occur concomitant with the continued presence of TIN2 at telomeres. The TIN2 domains were sensitive to DNase, but not RNase, occurred frequently, but not exclusively near nucleoli, and overlapped often with dense domains containing heterochromatin protein 1. Expression of truncated forms of TIN2 simultaneously prevented the formation of TIN2 domains and relaxed the stringent morphogenesis-induced growth arrest in human mammary epithelial cells. Here we show that a novel extra-telomeric organization of TIN2 is associated with the control of cell proliferation and identify TIN2 as an important regulator of mammary epithelial differentiation.

Key words: Nuclear structure, Three-dimensional culture, Breast, Morphogenesis, Quiescence, Heterochromatin protein 1

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