Download [2] Kee HJ*, Eom GH*, Joung H et al., Activation of histone

2014 MRC성과발표회
Abstract Information
[
] 심포지엄 구연 발표
[ ○ ] 기초의과학 학문후속세대 발표
Category (연제와 관련있는 분야에 모두 표시해 주십시오)
[
[
[
[
[
[
[
[
[
[
[
[
[
[
[
[
[○
[
[
[○
[
[
[
[
[
[
[
[
[
[
[
[
[
[
[○
[
[
[
[
[○
[
[
[
[
] Aging and age-related diseases
] Alternative medicine
] Anatomical methodology
] Anticancer strategies
] Bioengineering and technology
] Biology of development
] Biomarkers for personalized medicine
] Biomedical informatics
] Cancer biology (oncological sciences)
] Cellular injuries, death, apoptosis, autophagy
] Clinical pharmacology
] Craniofacial diseases
] Developmental Biology and Cell Differentiation
] DNA Replication, DNA Damage and Cell Cycle
] Drug: mechanism of action & toxicity
] Endocrinology and metabolism
] Enzyme: mechanism of action and regulation
] Gene expression
] Gene-, Cell-, & Immunotherapy
] Genetics and Epigenetics
] Gross anatomy
] Herb medicine and phytochemicals
] Histology of organs
] Immunology
] Inflammation and tissue injury
] Infectious diseases: bacteriology, virology and mycology
] Ion, ion channel & excitability
] Membrane transport & secretion
] Metabolic diseases
] Molecular and Cellular Aspects of Behaviour
] Neuroscience and Neurobiology
] Novel Targets for Drug Development and Screening Candidates
] Omics and Systems Biology
] Orofacial Diseases
] Protein Biochemistry: Structure, Function, and Modification
] Parasitology and parasitic diseases
] Pharmacogenetics
] Preventive medicine
] RNA Biology and Application
] Signal transduction
] Stem cells and regeneration
] Therapeutic approaches of Korean Medicine
] Vascular Biology and Medicine
] 기타 (
)
PP2A/HSP70 dynamically regulates HDAC2 phosphorylation and its
activity in cardiac hypertrophy
Gwang Hyeon Eom, Hyun-Ki Min, Duk-Hwa Kwon, Hyun Kook
Department of Pharmacology and Medical Research Center for Gene Regulation, Chonnam
National University Medical School, Gwangju 501-746, Republic of Korea
Rationale: Cardiac hypertrophy is an adaptation for increased hemodynamic demands by underlying
diseases and histone deacetylase (HDAC) 2 phosphorylation and following its activation are closely
associated with those of process [1, 2]. Recently, we have demonstrated that the acetylation of
HDAC2 K75 could induce S394 phosphorylation [3]; however, specific mechanism for intermodifications regulation in the single protein largely remains unclear.
Objective: We aimed to delineate the regulation mechanism how K75 acetylation modulates S394
phosphorylation and which phosphatase regulates HDAC2 phosphorylation in the cardiac
hypertrophy.
Methods and Results: We performed yeast-two-hybrid assay by use of HDAC2 as a bait and human
adult heart library as a prey and found that the regulatory subunit of protein phosphatase (PP) 2A
bound to HDAC2. In addition to the regulatory subunit, catalytic subunit of PP2A (PPP2CA) also
physically interacted with HDAC2 in the H9c2 cell, a cardiomyoblast cell line. PP2A kept HDAC2
unphosphorylated in the absence of hypertrophic stresses. Hypertrophic stresses-induced activation
of pCAF, however, induced HDAC2 K75 acetylation, which then allowed PP2A to dissociate from
HDAC2. This dissociation leads CK21 to bind to and phosphorylate HDAC2. Hypertrophic stresses
induced HSP70 which then preferentially bound to phosphorylated HDAC2 rather than to
unphosphorylated one. Forced expression of PPP2CA not only reduced enzyme activity of HDAC2
but inhibited hypertrophic response in the cardiomyocytes. On the other hand, HSP70 bound to
phosphorylated HDAC2 in order to mask the phosphor-HDAC2 from PPP2CA. HDAC2
phosphorylation and following activation of intrinsic activity were regulated by binding of PPP2CA to
HDAC2. PP2A functioned as a negative regulator for cardiac hypertrophy by targeting of HDAC2
S394 phosphorylation.
Conclusion: Taken together, HDAC2 forms a complex with PP2A in the absence of hypertrophic
stresses and remains inactivated. HDAC2 acetylation results in both detachment of PP2A and binding
of CK21 for phosphorylation, which is maintained by the association with HSP70 during
development of cardiac hypertrophy.
References
[1] Eom GH, Cho YK, Ko JH et al., Casein Kinase 21 induces hypertrophic response by
phosphorylation of HDAC2 S394 and its activation in the heart. Circulation 123(21):2392-2403, 2011
[2] Kee HJ*, Eom GH*, Joung H et al., Activation of histone deacetylase 2 by inducible heat shock
protein 70 in cardiac hypertrophy. Circ Res 103(11): 1259-1269, 2008 (co-first author)
[3] Eom GH, Nam YS, Oh JG et al., Regulation of Acetylation of Histone Deacetylase 2 by p300/CBPAssociated Factor/Histone Deacetylase 5 in the Development of Cardiac Hypertrophy. Circ Res
114:1133-1143, 2014
Keywords
Cardiac hypertrophy, posttranslational modifications, HDAC2, PP2A, HSP70
2014 MRC 성과발표회
Name : 엄광현
Affiliation : 전남대학교 의과대학 약리학교실
Position : 조교
E-mail : [email protected]
Field of Expertise : Epigenetic regulation
Education :
1999-2007
학사, 전남대학교 의과대학
2007-2009
석사, 전남대학교 대학원
2012-2014
박사, 전남대학교 대학원
Professional Experience :
2007-현재
조교, 전남대학교 의과대학 약리학교실
Selected Publications :
1. Nam YS, Kim Y, Joung H, Kwon DH, Choe N, Min HK, Kim YS, Kim HS, Kim DK, Cho YK, Kim
YH, Nam KI, Choi HC, Park DH, Suk K, Lee IK, Ahn Y, Lee CH, Choi HS, Eom GH*, Kook H*.
Small Heterodimer Partner Blocks Cardiac Hypertrophy by Interfering with GATA6 Signaling. Circ
Res. 115(5):493-503, 2014 (co-corresponding author)
2. Eom GH, Kook H. Posttranslational modifications of histone deacetylases: Implications for
cardiovascular diseases. Pharmacol Ther. 143(2):168-180, 2014
3. Eom GH, Nam YS, Oh JG, Choe N, Min HK, Yoo EK, Kang G, Nguyen VH, Min JJ, Kim JK, Lee
IK, Bassel-Duby R, Olson EN, Park WJ, Kook H. Regulation of Acetylation of Histone Deacetylase 2
by p300/CBP-Associated Factor/Histone Deacetylase 5 in the Development of Cardiac Hypertrophy.
Circ Res 114:1133-1143, 2014
4. Eom GH, Cho YK, Ko JH, Shin S, Choe N, Kim Y, Joung H, Kim HS, Nam KI, Kee HJ, Kook H.
Casein Kinase 21 induces hypertrophic response by phosphorylation of HDAC2 S394 and its
activation in the heart. Circulation 123(21):2392-2403, 2011
5. Kee HJ*, Eom GH*, Joung H, Shin S, Kim JR, Cho YK, Choe N, Sim BW, Jo D, Jeong MH, Kim
KK, Seo JS, Kook H. Activation of histone deacetylase 2 by inducible heat shock protein 70 in cardiac
hypertrophy. Circ Res 103(11): 1259-1269, 2008 (co-first author)