Specific inhibition of p300-HAT alters global gene expression and represses HIV replication.
Reversible acetylation of histone and nonhistone proteins plays pivotal role in cellular homeostasis. Dysfunction of histone acetyltransferases (HATs) leads to several diseases including cancer, neurodegenaration, asthma, diabetes, AIDS, and cardiac hypertrophy. We describe the synthesis and characterization of a set of p300-HAT-specific small-molecule inhibitors from a natural nonspecific HAT inhibitor, garcinol, which is highly toxic to cells. We show that the specific inhibitor selectively represses the p300-mediated acetylation of p53 in vivo. Furthermore, inhibition of p300-HAT down regulates several genes but significantly a few important genes are also upregulated. Remarkably, these inhibitors were found to be nontoxic to T cells, inhibit histone acetylation of HIV infected cells, and consequently inhibit the multiplication of HIV.
Mantelingu
K
K
Transcription and Disease Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Jakkur P.O. Bangalore, India.
Reddy
B A Ashok
BA
Swaminathan
V
V
Kishore
A Hari
AH
Siddappa
Nagadenahalli B
NB
Kumar
G V Pavan
GV
Nagashankar
G
G
Natesh
Nagashayana
N
Roy
Siddhartha
S
Sadhale
Parag P
PP
Ranga
Udaykumar
U
Narayana
Chandrabhas
C
Kundu
Tapas K
TK
D000107:Acetylation; D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects; D002843:Chromatin / Q000235:genetics; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects*; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D006367:HeLa Cells; D051548:Histone Acetyltransferases / Q000037:antagonists & inhibitors* / Q000235:genetics; D006657:Histones / Q000235:genetics; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D013601:T-Lymphocytes / Q000821:virology; D013729:Terpenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000235:genetics; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D015854:Up-Regulation; D014779:Virus Replication / Q000187:drug effects*; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor
D019380:Anti-HIV Agents; D018797:Cell Cycle Proteins; D002843:Chromatin; D004791:Enzyme Inhibitors; D051548:Histone Acetyltransferases; D006657:Histones; D013729:Terpenes; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C054597:garcinol