Bmi-1 regulates the Ink4a/Arf locus to control pancreatic β-cell proliferation

被引：185

作者：

Dhawan, Sangeeta ^{[1
]}

Tschen, Shuen-Ing ^{[1
]}

Bhushan, Anil ^{[1
,2
]}

机构：

[1] Univ Calif Los Angeles, Dept Med, Larry L Hillblom Islet Res Ctr, Los Angeles, CA 90024 USA

[2] Univ Calif Los Angeles, Inst Mol Biol, Los Angeles, CA 90024 USA

来源：

GENES & DEVELOPMENT | 2009年 / 23卷 / 08期

关键词：

MLL1; H2A ubiquitylation; aging; diabetes; regeneration; SELF-RENEWAL; ADULT; EXPRESSION; EXPANSION; PROTEINS;

D O I：

10.1101/gad.1742609

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

The molecular mechanisms that regulate the age-induced increase of p16(INK4a) expression associated with decreased beta-cell proliferation and regeneration are not well understood. We report that in aged islets, derepression of the Ink4a/Arf locus is associated with decreased Bmi-1 binding, loss of H2A ubiquitylation, increased MLL1 recruitment, and a concomitant increase in H3K4 trimethylation. During beta-cell regeneration these histone modifications are reversed resulting in reduced p16(INK4a) expression and increased proliferation. We suggest that PcG and TrxG proteins impart a combinatorial code of histone modifications on the Ink4a/Arf locus to control beta-cell proliferation during aging and regeneration.

引用

页码：906 / 911

页数：6

共 25 条

[1] The Polycomb group proteins bind throughout the INK4A-ARF locus and are disassociated in senescent cells
Bracken, Adrian P.
Kleine-Kohlbrecher, Daniela
Dietrich, Nikolaj
Pasini, Diego
Gargiulo, Gaetano
Beekman, Chantal
Theilgaard-Monch, Kim
Minucci, Saverio
Porse, Bo T.
Marine, Jean-Christophe
Hansen, Klaus H.
Helin, Kristian
[J]. GENES & DEVELOPMENT, 2007, 21 (05) : 525 - 530
[2] Ink4a and Arf differentially affect cell proliferation and neural stem cell self-renewal in Bmi1-deficient mice
Bruggeman, SWM
Valk-Lingbeek, ME
van der Stoop, PPM
Jacobs, JJL
Kieboom, K
Tanger, E
Hulsman, D
Leung, C
Arsenijevic, Y
Marino, S
van Lohuizen, M
[J]. GENES & DEVELOPMENT, 2005, 19 (12) : 1438 - 1443
[3] Role of Bmi-1 and Ring1A in H2A ubiquitylation and Hox gene silencing
Cao, R
Tsukada, Y
Zhang, Y
[J]. MOLECULAR CELL, 2005, 20 (06) : 845 - 854
[4] Adult pancreatic β-cells are formed by self-duplication rather than stem-cell differentiation
Dor, Y
Brown, J
Martinez, OI
Melton, DA
[J]. NATURE, 2004, 429 (6987) : 41 - 46
[5] The emerging genetic architecture of type 2 diabetes
Doria, Alessandro
Patti, Mary-Elizabeth
Kahn, C. Ronald
[J]. CELL METABOLISM, 2008, 8 (03) : 186 - 200
[6] Mammalian Trithorax and Polycomb-group homologues are antagonistic regulators of homeotic development
Hanson, RD
Hess, JL
Yu, BD
Ernst, P
van Lohuizen, M
Berns, A
van der Lugt, NMT
Shashikant, CS
Ruddle, FH
Seto, M
Korsmeyer, SJ
[J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1999, 96 (25) : 14372 - 14377
[7] Association of BMI1 with polycomb bodies is dynamic and requires PRC2/EZH2 and the maintenance DNA methyltransferase DNMT1
Hernández-Muñoz, I
Taghavi, P
Kuijl, C
Neefjes, J
van Lohuizen, M
[J]. MOLECULAR AND CELLULAR BIOLOGY, 2005, 25 (24) : 11047 - 11058
[8] The oncogene and Polycomb-group gene bmi-1 regulates cell proliferation and senescence through the ink4a locus
Jacobs, JJL
Kieboom, K
Marino, S
DePinho, RA
van Lohuizen, M
[J]. NATURE, 1999, 397 (6715) : 164 - 168
[9] Stem-cell ageing modified by the cyclin-dependent kinase inhibitor p16INK4a
Janzen, Viktor
Forkert, Randolf
Fleming, Heather E.
Saito, Yoriko
Waring, Michael T.
Dombkowski, David M.
Cheng, Tao
DePinho, Ronald A.
Sharpless, Norman E.
Scadden, David T.
[J]. NATURE, 2006, 443 (7110) : 421 - 426
[10] The regulation of INK4/ARF in cancer and aging
Kim, William Y.
Sharpless, Norman E.
[J]. CELL, 2006, 127 (02) : 265 - 275

← 1 2 3 →