TY - JOUR
T1 - Reduced body size and decreased intestinal tumor rates in HDAC2-mutant mice
AU - Zimmermann, Stephan
AU - Kiefer, Franz
AU - Prudenziati, Michela
AU - Spiller, Carmen
AU - Hansen, Jens
AU - Floss, Thomas
AU - Wurst, Wolfgang
AU - Minucci, Saverio
AU - Göttlicher, Martin
PY - 2007/10/1
Y1 - 2007/10/1
N2 - Histone deacetylases (HDAC) reverse the acetylation of histone and nonhistone proteins and thereby modulate chromatin structure and function of nonhistone proteins. Many tumor cell lines and experimental tumors respond to HDAC inhibition. To assess the role of an individual HDAC isoenzyme in physiology and tumor development, HDAC2-mutant mice were generated from a gene trap embryonic stem cell clone. These mice express a catalytically inactive fusion protein of the NH2-terminal part of HDAC2 and β-galactosidase,which fails to integrate into corepressor complexes with mSin3B. They are the first class 1 HDAC mutant mice that are viable although they are ∼25% smaller than their littermates. Cell number and thickness of intestinal mucosa are reduced. Mutant embryonic fibroblasts fail to respond to insulin-like growth factor I (IGF) by the IGF-I-induced increase in cell number observed in wild-type cells. These data suggest a novel link between HDACs and IGF-I-dependent responses. Crossing of HDAC2-mutant with tumor-prone APC min mice revealed tumor rates that are lower in HDAC2-deficient mice by 10% to 100% depending on segment of the gut and sex of the mice. These mice provide evidence that the key functions of HDAC2, although not essential for survival of the organism, play a rate-limiting role for tumor development in vivo.
AB - Histone deacetylases (HDAC) reverse the acetylation of histone and nonhistone proteins and thereby modulate chromatin structure and function of nonhistone proteins. Many tumor cell lines and experimental tumors respond to HDAC inhibition. To assess the role of an individual HDAC isoenzyme in physiology and tumor development, HDAC2-mutant mice were generated from a gene trap embryonic stem cell clone. These mice express a catalytically inactive fusion protein of the NH2-terminal part of HDAC2 and β-galactosidase,which fails to integrate into corepressor complexes with mSin3B. They are the first class 1 HDAC mutant mice that are viable although they are ∼25% smaller than their littermates. Cell number and thickness of intestinal mucosa are reduced. Mutant embryonic fibroblasts fail to respond to insulin-like growth factor I (IGF) by the IGF-I-induced increase in cell number observed in wild-type cells. These data suggest a novel link between HDACs and IGF-I-dependent responses. Crossing of HDAC2-mutant with tumor-prone APC min mice revealed tumor rates that are lower in HDAC2-deficient mice by 10% to 100% depending on segment of the gut and sex of the mice. These mice provide evidence that the key functions of HDAC2, although not essential for survival of the organism, play a rate-limiting role for tumor development in vivo.
UR - http://www.scopus.com/inward/record.url?scp=35148885660&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=35148885660&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-07-0312
DO - 10.1158/0008-5472.CAN-07-0312
M3 - Article
C2 - 17909008
AN - SCOPUS:35148885660
VL - 67
SP - 9047
EP - 9054
JO - Journal of Cancer Research
JF - Journal of Cancer Research
SN - 0008-5472
IS - 19
ER -