Higher-order nuclear organization in growth arrest of human mammary epithelial cells: a novel role for telomere-associated protein TIN2.
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 1gamma. 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.
Kaminker
Patrick
P
Buck Institute for Age Research, 8001 Redwood Boulevard, Novato, California 94945, USA.
Plachot
Cedric
C
Kim
Sahn-Ho
SH
Chung
Peter
P
Crippen
Danielle
D
Petersen
Ole W
OW
Bissell
Mina J
MJ
Campisi
Judith
J
Lelièvre
Sophie A
SA
D015153:Blotting, Western; D001940:Breast / Q000166:cytology*; D001973:Bromodeoxyuridine / Q000494:pharmacology; D018929:Cell Culture Techniques / Q000379:methods; D002454:Cell Differentiation; D002467:Cell Nucleus / Q000378:metabolism*; D049109:Cell Proliferation; D002478:Cells, Cultured; D003850:Deoxyribonuclease I / Q000378:metabolism; D003851:Deoxyribonucleases / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology* / Q000378:metabolism; D006570:Heterochromatin / Q000737:chemistry; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D019394:Ki-67 Antigen / Q000096:biosynthesis; D008856:Microscopy, Fluorescence; D010641:Phenotype; D017434:Protein Structure, Tertiary; D012190:Retroviridae / Q000235:genetics; D012259:Ribonuclease, Pancreatic / Q000378:metabolism; D012260:Ribonucleases / Q000378:metabolism; D016615:Telomere / Q000378:metabolism / Q000648:ultrastructure; D034501:Telomere-Binding Proteins / Q000378:metabolism*
D006570:Heterochromatin; D019394:Ki-67 Antigen; C440868:TINF2 protein, human; D034501:Telomere-Binding Proteins; D003851:Deoxyribonucleases; D012260:Ribonucleases; D003850:Deoxyribonuclease I; D012259:Ribonuclease, Pancreatic; D001973:Bromodeoxyuridine
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