title: Functional activity of RLIM/Rnf12 is regulated by phosphorylation-dependent nucleocytoplasmic shuttling.
abstract: The X-linked gene Rnf12 encodes the ubiquitin ligase really interesting new gene (RING) finger LIM domain-interacting protein (RLIM)/RING finger protein 12 (Rnf12), which serves as a major sex-specific epigenetic regulator of female mouse nurturing tissues. Early during embryogenesis, RLIM/Rnf12 expressed from the maternal allele is crucial for the development of extraembryonic trophoblast cells. In contrast, in mammary glands of pregnant and lactating adult females RLIM/Rnf12 expressed from the paternal allele functions as a critical survival factor for milk-producing alveolar cells. Although RLIM/Rnf12 is detected mostly in the nucleus, little is known about how and in which cellular compartment(s) RLIM/Rnf12 mediates its biological functions. Here we demonstrate that RLIM/Rnf12 protein shuttles between nucleus and cytoplasm and this is regulated by phosphorylation of serine S214 located within its nuclear localization sequence. We show that shuttling is important for RLIM to exert its biological functions, as alveolar cell survival activity is inhibited in cells expressing shuttling-deficient nuclear or cytoplasmic RLIM/Rnf12. Thus regulated nucleocytoplasmic shuttling of RLIM/Rnf12 coordinates cellular compartments during mammary alveolar cell survival.
authors.affiliation: Program in Gene Function and Expression, University of Massachusetts Medical School, Worcester, MA 01605-2324 Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605-2324 Centre for Molecular Neurobiology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany Institute for Tumor Biology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: Baowei
authors.initials: B
authors.lastname: Jiao
authors.forename: Naoko
authors.initials: N
authors.lastname: Taniguchi-Ishigaki
authors.forename: Cenap
authors.initials: C
authors.lastname: Güngör
authors.forename: Marvin A
authors.initials: MA
authors.lastname: Peters
authors.forename: Ya-Wen
authors.initials: YW
authors.lastname: Chen
authors.forename: Sabine
authors.initials: S
authors.lastname: Riethdorf
authors.forename: Alexander
authors.initials: A
authors.lastname: Drung
authors.forename: Leanne G
authors.initials: LG
authors.lastname: Ahronian
authors.forename: Jongdae
authors.initials: J
authors.lastname: Shin
authors.forename: Rachna
authors.initials: R
authors.lastname: Pagnis
authors.forename: Klaus
authors.initials: K
authors.lastname: Pantel
authors.forename: Taro
authors.initials: T
authors.lastname: Tachibana
authors.forename: Brian C
authors.initials: BC
authors.lastname: Lewis
authors.forename: Steven A
authors.initials: SA
authors.lastname: Johnsen
authors.forename: Ingolf
authors.initials: I
authors.lastname: Bach
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000235:genetics*; D000818:Animals; D002467:Cell Nucleus / Q000235:genetics; D002470:Cell Survival / Q000235:genetics*; D047108:Embryonic Development; D044127:Epigenesis, Genetic / Q000235:genetics; D005260:Female; D006367:HeLa Cells; D006801:Humans; D060588:LIM Domain Proteins / Q000235:genetics / Q000378:metabolism; D008321:Mammary Glands, Animal / Q000378:metabolism*; D051379:Mice; D010766:Phosphorylation; D011247:Pregnancy; D019849:Sex Determination Processes; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
chemical_list: D060588:LIM Domain Proteins; C492370:RLIM protein, human; D044767:Ubiquitin-Protein Ligases
references.citation: Sci Signal. 2010 Jan 12;3(104):ra3
references.pmid: 20068231
references.citation: Nature. 2002 Mar 7;416(6876):99-103
references.pmid: 11882901
references.citation: Mech Dev. 2000 Mar 1;91(1-2):5-17
references.pmid: 10704826
references.citation: PLoS Genet. 2011 Jan 27;7(1):e1002001
references.pmid: 21298085
references.citation: RNA. 2000 Sep;6(9):1197-211
references.pmid: 10999598
references.citation: Mol Cell. 2007 Dec 14;28(5):730-8
references.pmid: 18082598
references.citation: Oncogene. 2004 Feb 26;23(8):1507-13
references.pmid: 14676840
references.citation: Proc Natl Acad Sci U S A. 2005 Oct 18;102(42):15042-7
references.pmid: 16210245
references.citation: Genomics. 2000 Oct 1;69(1):120-30
references.pmid: 11013082
references.citation: Nature. 2012 Apr 29;485(7398):386-90
references.pmid: 22596162
references.citation: Dev Dyn. 2006 Mar;235(3):786-91
references.pmid: 16395690
references.citation: Cold Spring Harb Perspect Biol. 2010 Apr;2(4):a000620
references.pmid: 20452941
references.citation: Annu Rev Microbiol. 1998;52:491-532
references.pmid: 9891806
references.citation: Science. 2001 Sep 7;293(5536):1836-9
references.pmid: 11546874
references.citation: Nat Genet. 1999 Aug;22(4):394-9
references.pmid: 10431247
references.citation: Genes Dev. 2005 Oct 1;19(19):2307-19
references.pmid: 16204183
references.citation: Nat Rev Mol Cell Biol. 2011 Jun 23;12(7):439-52
references.pmid: 21697901
references.citation: Proc Natl Acad Sci U S A. 2001 Dec 4;98(25):14452-7
references.pmid: 11734645
references.citation: Cell. 2012 Apr 27;149(3):630-41
references.pmid: 22541433
references.citation: Proc Natl Acad Sci U S A. 1999 Aug 3;96(16):9112-7
references.pmid: 10430904
references.citation: Cell. 2009 Nov 25;139(5):999-1011
references.pmid: 19945382
references.citation: Nucleic Acids Res. 1997 Nov 1;25(21):4323-30
references.pmid: 9336464
references.citation: Annu Rev Biochem. 2001;70:503-33
references.pmid: 11395416
references.citation: Curr Opin Cell Biol. 2006 Oct;18(5):524-32
references.pmid: 16908128
references.citation: PLoS One. 2009 Aug 06;4(8):e6529
references.pmid: 19657394
references.citation: Cancer Res. 2009 Jan 1;69(1):128-36
references.pmid: 19117995
references.citation: Genes Dev. 1997 Jun 1;11(11):1370-80
references.pmid: 9192866
references.citation: Proc Natl Acad Sci U S A. 2007 Sep 18;104(38):15000-5
references.pmid: 17848518
references.citation: Cancer Res. 2007 Aug 15;67(16):7589-96
references.pmid: 17699762
references.citation: J Biol Chem. 2009 Mar 27;284(13):8557-66
references.pmid: 19164295
references.citation: Trends Biochem Sci. 2003 Apr;28(4):189-95
references.pmid: 12713902
references.citation: Mol Cell. 2012 Jun 8;46(5):650-61
references.pmid: 22560923
references.citation: Nature. 2010 Oct 21;467(7318):977-81
references.pmid: 20962847
references.citation: Methods Mol Med. 2004;88:133-9
references.pmid: 14634224
references.citation: EMBO J. 2003 Jul 1;22(13):3411-20
references.pmid: 12840003
references.citation: J Cell Biol. 2008 Mar 24;180(6):1061-4
references.pmid: 18347069
references.citation: Cancer Cell. 2009 Apr 7;15(4):270-82
references.pmid: 19345326
references.citation: Biochem Biophys Res Commun. 2011 Oct 14;414(1):181-5
references.pmid: 21945933
references.citation: Nat Rev Mol Cell Biol. 2004 Nov;5(11):920-31
references.pmid: 15520811
references.citation: EMBO J. 1999 May 4;18(9):2593-609
references.pmid: 10228171
references.citation: Mol Endocrinol. 1990 Apr;4(4):597-603
references.pmid: 1704103