◀ Back to CDKN1A
CDKN1A — HDAC2
Pathways - manually collected, often from reviews:
-
NCI Pathway Database Direct p53 effectors:
HDAC2 (HDAC2)
→
p21CIP1 (CDKN1A)
(transcription, inhibits)
Le Cam et al., Cell 2006, Harms et al., Cancer Res 2007, Shi et al., Mol Cell 2007, Das et al., Cell 2007, Xu et al., J Biol Chem 2007, Gamper et al., Mol Cell Biol 2008, el-Deiry et al., Cancer Res 1995
Evidence: mutant phenotype, reporter gene, physical interaction
-
NCI Pathway Database Direct p53 effectors:
HDAC2 (HDAC2)
→
p21CIP1 (CDKN1A)
(transcription, inhibits)
Harms et al., Cancer Res 2007, Shi et al., Mol Cell 2007, Das et al., Cell 2007, Xu et al., J Biol Chem 2007, Gamper et al., Mol Cell Biol 2008, Tang et al., Cell 2008, el-Deiry et al., Cancer Res 1995
Evidence: mutant phenotype, reporter gene, physical interaction
-
NCI Pathway Database Direct p53 effectors:
HDAC2 (HDAC2)
→
p21CIP1 (CDKN1A)
(transcription, inhibits)
Harms et al., Cancer Res 2007, Shi et al., Mol Cell 2007, Das et al., Cell 2007, Xu et al., J Biol Chem 2007, Gamper et al., Mol Cell Biol 2008, Jansson et al., Nat Cell Biol 2008, el-Deiry et al., Cancer Res 1995
Evidence: mutant phenotype, reporter gene, physical interaction
Protein-Protein interactions - manually collected from original source literature:
Studies that report less than 10 interactions are marked with *
Text-mined interactions from Literome
Xiao et al., J Cell Biochem 1999
:
Both Sp1 and Sp3 are responsible for
p21waf1 promoter activity
induced by
histone deacetylase inhibitor in NIH3T3 cells
Sowa et al., Cancer Res 1999
:
Sp3, but not Sp1, mediates the transcriptional
activation of the
p21/WAF1/Cip1 gene promoter by
histone deacetylase inhibitor
Xiao et al., J Biol Chem 2000
:
p300 collaborates with Sp1 and Sp3 in
p21 ( waf1/cip1 ) promoter activation
induced by
histone deacetylase inhibitor
Shin et al., Cancer Res 2000
(Stomach Neoplasms) :
The
p21 gene was
activated only by
histone deacetylase inhibitor
Claassen et al., Proc Natl Acad Sci U S A 2000
:
Repression of
p21 ( CIP1 ) transcription by c-Myc occurred at the promoter level in a region near the start site of transcriptional initiation and was
independent of
histone deacetylase activity
Huang et al., Oncogene 2000
(Breast Neoplasms) :
Activation of the
p21WAF1/CIP1 promoter independent of p53 by the
histone deacetylase inhibitor suberoylanilide hydroxamic acid ( SAHA ) through the Sp1 sites
Sowa et al., Biofactors 2000
(Colorectal Neoplasms...) :
As a model of this, we found that
histone deacetylase inhibitors such as butyrate or trichostatin A dramatically
stimulate the
p21/WAF1 gene promoter through the Spl sites, resulting in cell cycle arrest
Han et al., J Biol Chem 2001
:
Activation of
p21 ( WAF1/Cip1 ) transcription through Sp1 sites by
histone deacetylase inhibitor apicidin : involvement of protein kinase C
Burgess et al., Mol Pharmacol 2001
:
Up-regulation of
p21 ( WAF1/CIP1 ) by
histone deacetylase inhibitors reduces their cytotoxicity
Blagosklonny et al., Mol Cancer Ther 2002
:
By preventing deacetylation of histones,
histone deacetylase inhibitors ( HDIs ) transcriptionally
induce p21
Ju et al., Cancer Res 2003
(Ataxia Telangiectasia) :
In this work, we show that
p21 ( WAF1 )
induction by
HDAC inhibitors ( depsipeptide and trichostatin A ) is defective in Ataxia telangiectasia ( AT ) cells but normal in matched wild-type ( WT ) cells ( human diploid fibroblasts ) ... To verify the role of ATM in this effect, we show that ectopic expression of the WT ATM gene in an AT cell line fully restores
p21 ( WAF1 )
induction by the
HDAC inhibitors
Sowa et al., Nihon Eiseigaku Zasshi 2003
(Neoplasms) :
As a model of our hypothesis, we found that
histone deacetylase inhibitors such as butyrate and trichostatin A dramatically
stimulate the
p21/WAF1 gene promoter through the Sp1 sites, resulting in cell cycle arrest
Davie et al., J Nutr 2003
(Breast Neoplasms) :
A model is proposed in which inhibition of Sp1/Sp3 associated
HDAC activity
leads to histone hyperacetylation and transcriptional activation of the
p21 ( Waf1/Cip1 ) gene ; p21 ( Waf1/Cip1 ) inhibits cyclin dependent kinase 2 activity and thereby arrests cell cycling
Barnes et al., Nat Struct Biol 2003
:
We describe here the binding, phosphorylation and functional
regulation of
CtBP by the
p21 activated kinase 1 (Pak1)
Donadelli et al., Mol Carcinog 2003
(Adenocarcinoma...) :
In cells with an altered p53 gene, the expression of
p21 ( WAF1/CIP1 ), a potent inhibitor of cyclin dependent kinases, can be
induced by
histone deacetylase (HDAC) inhibitors via a p53 independent pathway, which may play a critical role in arrest of cell growth
Chung et al., Mol Ther 2003
(Arthritis, Rheumatoid...) :
We found that the
histone deacetylase (HDAC) inhibitors ( phenylbutyrate and trichostatin A ) causing histone hyperacetylation to modulate multiple gene expression not only
induced the expression of
p21 ( Cip1 ) and p16(INK4) in synovial cells but also inhibited the expression of tumor necrosis factor-alpha in affected tissues in adjuvant arthritis, an animal model of RA
Gui et al., Proc Natl Acad Sci U S A 2004
:
Histone deacetylase (HDAC) inhibitor
activation of
p21WAF1 involves changes in promoter associated proteins, including HDAC1
Piekarz et al., Blood 2004
(Lymphoma, T-Cell) :
Treatment with depsipeptide, as well as other
histone deacetylase inhibitors,
caused induction of histone acetylation, induction of
p21 expression, and substantial apoptosis without significant cell cycle arrest
Chen et al., Zhonghua Yi Xue Za Zhi 2004
(Colonic Neoplasms) :
In these two human colon cancer cell lines,
HDAC inhibitors
stimulate the
p21 ( WAF1 ) gene expression by selectively increasing the degree of acetylation of the gene associated histones, and induce a G ( 1 ) cell cycle arrest
Li et al., Biochem Biophys Res Commun 2004
(Uterine Cervical Neoplasms) :
However, the exact mechanism by which
HDAC inhibitors
induce p21WAF1/CIP1 remains unclear
Zhu et al., Cell cycle (Georgetown, Tex.) 2004
:
Whereas inhibition of HDACs by valproic acid or trichostatin A increases p21 expression, selective interference with
HDAC2 by siRNA transfection or reconstitution of wildtype APC does not
affect p21 expression
Varshochi et al., J Biol Chem 2005
(Breast Neoplasms) :
The fact that
p21Waf1 expression is normally
repressed by
HDAC activity in cycling cells is further demonstrated by the finding that p21Waf1 transcription can be induced by the silencing of HDACs with small interfering RNA or treatment with HDAC inhibitors
Rocchi et al., Oncol Rep 2005
(Neuroblastoma) :
p21Waf1/Cip1 is a common target
induced by short-chain fatty acid
HDAC inhibitors ( valproic acid, tributyrin and sodium butyrate ) in neuroblastoma cells
Myzak et al., FASEB J 2006
(Cell Transformation, Neoplastic...) :
In mice treated with a single oral dose of 10 mumol SFN, there was significant inhibition of
HDAC activity in the colonic mucosa after 6 h, and immunoblots revealed a concomitant increase in acetylated histones H3 and H4, which returned to control levels by 48 h. Longer-term treatment with SFN in the diet
resulted in levels of acetylated histones and
p21 ( WAF1 ) in the ileum, colon, prostate, and peripheral blood mononuclear cells that were elevated compared with controls
Zhao et al., Mol Cell Biol 2006
:
Here we found that an inhibitor of
HDAC , depsipeptide ( FR901228 ), but not trichostatin A (TSA),
induces p21 ( Waf1/Cip1 ) expression through both p53 and Sp1/Sp3 pathways in A549 cells ( which retain wild-type p53 )
Ocker et al., Int J Biochem Cell Biol 2007
:
Several studies have shown that
HDAC inhibitors strongly
activate the expression of the cyclin dependent kinase inhibitor
p21 ( cip1/waf1 ) through ( i ) enhanced histone acetylation around the p21 ( cip1/waf1 ) promoter and ( ii ) the Sp1 sites on the p21 ( cip1/waf1 ) promoter releasing the repressor HDAC1 from its binding
Sun et al., Proc Natl Acad Sci U S A 2007
:
Either inhibition of
HDAC activity or knockdown of HDAC expression
led to marked induction of
p21 and pten gene expression and dramatically reduced neural stem cell proliferation, suggesting that the TLX interacting HDACs play an important role in neural stem cell proliferation
Condorelli et al., Br J Pharmacol 2008
(Neuroblastoma) :
Accordingly,
HDAC inhibitor induced cell killing and
p21/Waf1/Cip1 upregulation is
impaired in p53i-cells
Liu et al., Cancer Res 2009
(Breast Neoplasms) :
Short hairpin RNA silencing of either
HDAC2 or HDAC4 is
sufficient to induce
p21 expression
Chehl et al., HPB (Oxford) 2009
:
Tq also increased
p21 WAF1 expression,
inhibited histone deacetylase (HDAC) activity, and induced histone hyperacetylation
Yamaguchi et al., Cancer Sci 2010
(Gallbladder Neoplasms) :
In TGBC2TKB cells, the expression of EZH2 and
HDAC1/2 were decreased by SAHA treatment, and p16(INK4a), E-cadherin, and
p21were simultaneously
activated ; however, no such findings were obtained in HGECs, suggesting that the effect of SAHA depends on the EZH2 mediated tumor suppressor loss
Yamaguchi et al., Genes Dev 2010
:
These results indicate that HDAC1 and
HDAC2 , by normally repressing the expression of
p21 and p57,
regulate the G1-to-S-phase transition of the cell cycle
Madison et al., Oncogene 2010
:
PARP inhibition attenuated activation of
p21 transcription by both p53 independent and p53 dependent processes, in a
CtBP dependent manner
Simboeck et al., J Biol Chem 2010
(MAP Kinase Signaling System) :
Taken together we have revealed a cross-talk of reversible phosphorylation and acetylation signals that controls the
activation of
p21 by
HDAC inhibitors and identify the phosphatase PP2A as chromatin associated transcriptional repressor in mammalian cells
Clarke et al., Mol Nutr Food Res 2011
(Hyperplasia...) :
SFN treatment also selectively decreased
HDAC activity, and Class I and II HDAC proteins, increased acetylated histone H3 at the promoter for P21,
induced p21 expression and increased tubulin acetylation in prostate cancer cells
Zheng et al., Cell Res 2011
:
Interference with
HDAC2 phosphorylation by either CK2a knockdown or the use of phosphorylation-deficient mutant of HDAC2 prevents the dissociation of Klf5 from the p21 promoter and
impairs RAR agonist induced
p21 activation
Matsuzaki et al., Environ Health Prev Med 2003
:
Previously, we demonstrated that
HDAC inhibitors, such as sodium butyrate and trichostatin A (TSA), transcriptionally
induce the cyclin dependent kinase inhibitor
p21 ( WAF1/Cip1 ), a downstream target gene of p53, in a p53 independent manner
Jung et al., J Cell Biochem 2012
(Lung Neoplasms) :
In addition, we demonstrated that
HDAC2 directly
regulated p21WAF1/CIP1 expression in a p53 independent manner
Hua et al., Zhonghua Bing Li Xue Za Zhi 2012
:
Furthermore, Western blot demonstrated that down-regulation of
HDAC2 expression decreased the expression of cyclin D1, cyclin E and CDK2 proteins but
increased the expression of
p21 protein
Bellucci et al., PloS one 2013
(Breast Neoplasms) :
Activation of
p21 by
HDAC inhibitors requires acetylation of H2A.Z
Sachweh et al., Cell death & disease 2013
:
Incompatible
effects of p53 and
HDAC inhibition on
p21 expression and cell cycle progression