title: Higher-order nuclear organization in growth arrest of human mammary epithelial cells: a novel role for telomere-associated protein TIN2.
abstract: 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.
authors.affiliation: Buck Institute for Age Research, 8001 Redwood Boulevard, Novato, California 94945, USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: Kaminker
authors.forename: Cedric
authors.initials: C
authors.lastname: Plachot
authors.forename: Sahn-Ho
authors.initials: SH
authors.lastname: Kim
authors.forename: Peter
authors.initials: P
authors.lastname: Chung
authors.forename: Danielle
authors.initials: D
authors.lastname: Crippen
authors.forename: Ole W
authors.initials: OW
authors.lastname: Petersen
authors.forename: Mina J
authors.initials: MJ
authors.lastname: Bissell
authors.forename: Judith
authors.initials: J
authors.lastname: Campisi
authors.forename: Sophie A
authors.initials: SA
authors.lastname: Lelièvre
mesh_terms: 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*
chemical_list: 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
references.citation: Curr Opin Cell Biol. 2003 Dec;15(6):753-62
references.pmid: 14644202
references.citation: EMBO Rep. 2003 Jul;4(7):685-91
references.pmid: 12835755
references.citation: Nat Rev Mol Cell Biol. 2004 Apr;5(4):323-9
references.pmid: 15071557
references.citation: Nat Cell Biol. 2004 Jul;6(7):673-80
references.pmid: 15181449
references.citation: Exp Cell Res. 2004 Aug 1;298(1):122-32
references.pmid: 15242767
references.citation: Proc Natl Acad Sci U S A. 1984 Sep;81(17):5435-9
references.pmid: 6591199
references.citation: J Biol Chem. 2004 Oct 15;279(42):43799-804
references.pmid: 15292264
references.citation: Genes Dev. 2004 Jul 15;18(14):1649-54
references.pmid: 15231715
references.citation: In Vitro Cell Dev Biol. 1987 Mar;23(3):181-8
references.pmid: 3558253
references.citation: Virchows Arch B Cell Pathol Incl Mol Pathol. 1988;56(1):25-33
references.pmid: 2907198
references.citation: Nature. 1990 May 31;345(6274):458-60
references.pmid: 2342578
references.citation: Proc Natl Acad Sci U S A. 1992 Oct 1;89(19):9064-8
references.pmid: 1384042
references.citation: Exp Cell Res. 1993 Sep;208(1):175-88
references.pmid: 7689475
references.citation: Science. 1995 Dec 8;270(5242):1663-7
references.pmid: 7502076
references.citation: Hum Mol Genet. 1996 May;5(5):685-91
references.pmid: 8733138
references.citation: Genes Dev. 1996 Jul 15;10(14):1796-811
references.pmid: 8698239
references.citation: J Cell Biol. 1996 Sep;134(6):1349-63
references.pmid: 8830766
references.citation: J Cell Biol. 1996 Nov;135(4):867-81
references.pmid: 8922373
references.citation: Experientia. 1996 Dec 15;52(12):1136-47
references.pmid: 8988257
references.citation: Nature. 1997 Feb 20;385(6618):740-3
references.pmid: 9034193
references.citation: J Cell Biol. 1997 Apr 7;137(1):231-45
references.pmid: 9105051
references.citation: Exp Cell Res. 1997 Apr 10;232(1):29-41
references.pmid: 9141618
references.citation: Nat Genet. 1997 Oct;17(2):236-9
references.pmid: 9326951
references.citation: Oncogene. 1998 Mar 5;16(9):1217-22
references.pmid: 9528864
references.citation: Proc Natl Acad Sci U S A. 1998 Dec 8;95(25):14711-6
references.pmid: 9843954
references.citation: Nat Genet. 1999 Dec;23(4):405-12
references.pmid: 10581025
references.citation: J Gen Virol. 1999 Nov;80 ( Pt 11):2889-900
references.pmid: 10580050
references.citation: Crit Rev Eukaryot Gene Expr. 2000;10(1):13-20
references.pmid: 10813390
references.citation: Cell. 2000 May 26;101(5):471-83
references.pmid: 10850490
references.citation: J Cell Biol. 2000 Dec 25;151(7):1591-8
references.pmid: 11134086
references.citation: Curr Opin Genet Dev. 2001 Apr;11(2):167-74
references.pmid: 11250140
references.citation: J Biol Chem. 2001 Mar 16;276(11):8321-7
references.pmid: 11112778
references.citation: Hum Mol Genet. 2001 Dec 15;10(26):3017-24
references.pmid: 11751684
references.citation: J Cell Sci. 2002 Jan 1;115(Pt 1):39-50
references.pmid: 11801722
references.citation: Mol Cell Biol. 2002 Aug;22(15):5259-69
references.pmid: 12101223
references.citation: Int J Biochem Cell Biol. 2002 Nov;34(11):1382-94
references.pmid: 12200033
references.citation: Int Rev Cytol. 2002;219:199-266
references.pmid: 12211630
references.citation: Cancer Cell. 2002 Sep;2(3):205-16
references.pmid: 12242153
references.citation: Proc Natl Acad Sci U S A. 2002 Dec 10;99 Suppl 4:16462-9
references.pmid: 12151603
references.citation: Curr Top Microbiol Immunol. 2003;274:53-77
references.pmid: 12596904
references.citation: Genomics. 2003 Apr;81(4):422-32
references.pmid: 12676566
references.citation: Mol Cell Biol. 2004 Jan;24(2):595-607
references.pmid: 14701733