Common regulation of growth arrest and differentiation of osteoblasts by helix-loop-helix factors

被引:104
作者
Funato, N [1 ]
Ohtani, K [1 ]
Ohyama, K [1 ]
Kuroda, T [1 ]
Nakamura, M [1 ]
机构
[1] Tokyo Med & Dent Univ, Human Gene Sci Ctr, Bunkyo Ku, Tokyo 1138510, Japan
关键词
D O I
10.1128/MCB.21.21.7416-7428.2001
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Cellular differentiation entails the coordination of cell cycle arrest and tissue-specific gene expression. We investigated the involvement of basic helix-loop-helix (bHLH) factors in differentiation of osteoblasts using the human osteoblastic cell line MG63. Serum starvation induced growth arrest at G, phase, accompanied by expression of cyclin-dependent kinase inhibitor p21(WAF1/Cip1). Reporter assays with the p21 gene promoter demonstrated that the combination of E2A (E12 or E47) and coactivator CBP was responsible for p21 induction independent of p53. Twist inhibited E2A-CBP-dependent activation of the exogenous and endogenous p21 promoters. Ids similarly inhibited the exogenously transfected p21 promoter; however less antagonistic effect on the endogenous p21 promoter was observed. Twist was predominantly present in nuclei in MG63 cells growing in complete medium, while it localized mainly in the cytoplasm after serum starvation. The fibroblast growth factor receptor 3 gene (FGFR3), which generates signals leading to differentiation of osteoblasts, was found to be controlled by the same transcriptional regulation as the p21 gene. E2A and Twist influenced alkaline phosphatase expression, a consensus marker of osteoblast differentiation. Expression of E2A and FGFR3 was seen at the location of osteoblast differentiation in the calvaria of mouse embryos, implicating bHLH molecules in physiological osteoblast differentiation. These results demonstrate that a common regulatory system is involved in at least two distinct steps in osteoblastic differentiation. Our results also provide the molecular basis of Saethre-Chotzen syndrome, caused by mutations of the TWIST and FGFR3 genes.
引用
收藏
页码:7416 / 7428
页数:13
相关论文
共 73 条
[11]   PHOSPHORYLATED CREB BINDS SPECIFICALLY TO THE NUCLEAR-PROTEIN CBP [J].
CHRIVIA, JC ;
KWOK, RPS ;
LAMB, N ;
HAGIWARA, M ;
MONTMINY, MR ;
GOODMAN, RH .
NATURE, 1993, 365 (6449) :855-859
[12]   EXPRESSION OF THE NOVEL BASIC HELIX-LOOP-HELIX GENE EHAND IN NEURAL CREST DERIVATIVES AND EXTRAEMBRYONIC MEMBRANES DURING MOUSE DEVELOPMENT [J].
CSERJESI, P ;
BROWN, D ;
LYONS, GE ;
OLSON, EN .
DEVELOPMENTAL BIOLOGY, 1995, 170 (02) :664-678
[13]   TRANSFORMING GROWTH-FACTOR-BETA INDUCES THE CYCLIN-DEPENDENT KINASE INHIBITOR P21 THROUGH A P53-INDEPENDENT MECHANISM [J].
DATTO, MB ;
LI, Y ;
PANUS, JF ;
HOWE, DJ ;
XIONG, Y ;
WANG, XF .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1995, 92 (12) :5545-5549
[14]   MICE DEFICIENT FOR P53 ARE DEVELOPMENTALLY NORMAL BUT SUSCEPTIBLE TO SPONTANEOUS TUMORS [J].
DONEHOWER, LA ;
HARVEY, M ;
SLAGLE, BL ;
MCARTHUR, MJ ;
MONTGOMERY, CA ;
BUTEL, JS ;
BRADLEY, A .
NATURE, 1992, 356 (6366) :215-221
[15]   P53-DEPENDENT INHIBITION OF CYCLIN-DEPENDENT KINASE-ACTIVITIES IN HUMAN FIBROBLASTS DURING RADIATION-INDUCED G1 ARREST [J].
DULIC, V ;
KAUFMANN, WK ;
WILSON, SJ ;
TLSTY, TD ;
LEES, E ;
HARPER, JW ;
ELLEDGE, SJ ;
REED, SI .
CELL, 1994, 76 (06) :1013-1023
[16]   Interaction and functional collaboration of p300/CBP and bHLH proteins in muscle and B-cell differentiation [J].
Eckner, R ;
Yao, TP ;
Oldread, E ;
Livingston, DM .
GENES & DEVELOPMENT, 1996, 10 (19) :2478-2490
[17]   WAF1, A POTENTIAL MEDIATOR OF P53 TUMOR SUPPRESSION [J].
ELDEIRY, WS ;
TOKINO, T ;
VELCULESCU, VE ;
LEVY, DB ;
PARSONS, R ;
TRENT, JM ;
LIN, D ;
MERCER, WE ;
KINZLER, KW ;
VOGELSTEIN, B .
CELL, 1993, 75 (04) :817-825
[18]  
ElGhouzzi V, 1997, NAT GENET, V15, P42
[19]  
FUCHTBAUER EM, 1995, DEV DYNAM, V204, P316
[20]  
Funato N, 1998, LAB INVEST, V78, P477