Histone deacetylase inhibition-mediated post-translational elevation of p27kip1 protein levels is required for G1 arrest in fibroblasts

被引:36
作者
Chen, JS
Faller, DV
机构
[1] Boston Univ, Sch Med, Ctr Canc Res, Dept Med, Boston, MA 02118 USA
[2] Boston Univ, Sch Med, Ctr Canc Res, Dept Biochem, Boston, MA 02118 USA
[3] Boston Univ, Sch Med, Ctr Canc Res, Dept Pathol, Boston, MA 02118 USA
[4] Boston Univ, Sch Med, Ctr Canc Res, Dept Microbiol, Boston, MA 02118 USA
关键词
D O I
10.1002/jcp.20094
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Butyrate, a non-toxic short-chain fatty acid (SCFA) and inhibitor of histone deacetylase (HDAC), has potential as an anti-tumor agent because it imposes a reversible G(1) block in normal cells yet induces apoptosis in tumor lines. As a potent reactivator of fetal globin transcription, butyrate is used clinically in the treatment of hemoglobinopathies. The anti-proliferative effect of butyrate and its derivatives on in vivo erythroid cell maturation, however, has limited their utility. The molecular mechanisms underlying the G, arrest induced by butyrate and related SCFAs remain unclear. One model, drawing on tumor cell data, proposes that HDAC inhibition and subsequent transcriptional induction of cyclin-dependent kinase inhibitor (CKI) p21(CIP) are required. However, because of potentially confounding genetic mutations present in tumor models, we examined SCFA effects on CKIs in a non-transformed growth control model. Using murine 3T3 fibroblasts, we find p27(KIP1) is also strongly induced. Unlike previously described effects of butyrate and HDAC inhibition on p21(CIP), p27(KIP1) induction did not occur at the transcriptional level; instead, the stability of the p27(KIP1) protein increased. Other structurally unrelated HDAC inhibitors, including trichostatin A (TSA), induced p27(KIP1) Similarly. p27(KIP1) was found in cyclin E/Cdk2 complexes, concomitant with suppression of cdk2 activity. Elevation of p27(KIP1) is required for the observed G(1) blockade, as p27(KIP1)-deficient fibroblasts were resistant to HDAC inhibition-induced arrest. These data suggest a novel activity for HDAC inhibitors and demonstrate a critical role for p27(KIP1) in mediating G(1) arrest in response to these drugs. (C) 2004 Wiley-Liss, Inc.
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页码:87 / 99
页数:13
相关论文
共 73 条
[1]   p21WAF1 is required for butyrate-mediated growth inhibition of human colon cancer cells [J].
Archer, SY ;
Meng, SF ;
Shei, A ;
Hodin, RA .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1998, 95 (12) :6791-6796
[2]  
Atweh GF, 1999, BLOOD, V93, P1790
[3]  
BOFFA LC, 1992, CANCER RES, V52, P5906
[4]   Abrogation of IL-3 requirements and stimulation of hematopoietic cell proliferation in vitro and in vivo by carboxylic acids [J].
Boosalis, MS ;
Ikuta, T ;
Pace, BS ;
da Fonseca, S ;
White, GL ;
Faller, DV ;
Perrine, SP .
BLOOD CELLS MOLECULES AND DISEASES, 1997, 23 (23) :434-442
[5]   Short-chain fatty acid derivatives stimulate cell proliferation and induce STAT-5 activation [J].
Boosalis, MS ;
Bandyopadhyay, R ;
Bresnick, EH ;
Pace, BS ;
Van DeMark, K ;
Zhang, BH ;
Faller, DV ;
Perrine, SP .
BLOOD, 2001, 97 (10) :3259-3267
[6]   RESTRICTION POINT CONTROL OF CELL-GROWTH BY A LABILE PROTEIN - EVIDENCE FOR INCREASED STABILITY IN TRANSFORMED-CELLS [J].
CAMPISI, J ;
MEDRANO, EE ;
MORREO, G ;
PARDEE, AB .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA-BIOLOGICAL SCIENCES, 1982, 79 (02) :436-440
[7]   SKP2 is required for ubiquitin-mediated degradation of the CDK inhibitor p27 [J].
Carrano, AC ;
Eytan, E ;
Hershko, A ;
Pagano, M .
NATURE CELL BIOLOGY, 1999, 1 (04) :193-199
[8]   Short-Chain Fatty Acid Inhibitors of Histone Deacetylases: Promising Anticancer Therapeutics? [J].
Chen, James S. ;
Faller, Douglas V. ;
Spanjaard, Remco A. .
CURRENT CANCER DRUG TARGETS, 2003, 3 (03) :219-236
[9]   HUMAN P68 KINASE EXHIBITS GROWTH SUPPRESSION IN YEAST AND HOMOLOGY TO THE TRANSLATIONAL REGULATOR GCN2 [J].
CHONG, KL ;
FENG, L ;
SCHAPPERT, K ;
MEURS, E ;
DONAHUE, TF ;
FRIESEN, JD ;
HOVANESSIAN, AG ;
WILLIAMS, BRG .
EMBO JOURNAL, 1992, 11 (04) :1553-1562
[10]   Requirement of p27(Kip1) for restriction point control of the fibroblast cell cycle [J].
Coats, S ;
Flanagan, WM ;
Nourse, J ;
Roberts, JM .
SCIENCE, 1996, 272 (5263) :877-880