Specific inhibition of p300-HAT alters global gene expression and represses HIV replication

K Mantelingu; B A Ashok Reddy; V Swaminathan; A Hari Kishore; Nagadenahalli B Siddappa; G V Pavan Kumar; G Nagashankar; Nagashayana Natesh; Siddhartha Roy; Parag P Sadhale; Udaykumar Ranga; Chandrabhas Narayana; Tapas K Kundu

doi:10.1016/j.chembiol.2007.04.011

Specific inhibition of p300-HAT alters global gene expression and represses HIV replication

Chem Biol. 2007 Jun;14(6):645-57. doi: 10.1016/j.chembiol.2007.04.011.

Authors

K Mantelingu¹, B A Ashok Reddy, V Swaminathan, A Hari Kishore, Nagadenahalli B Siddappa, G V Pavan Kumar, G Nagashankar, Nagashayana Natesh, Siddhartha Roy, Parag P Sadhale, Udaykumar Ranga, Chandrabhas Narayana, Tapas K Kundu

Affiliation

¹ Transcription and Disease Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Jakkur P.O. Bangalore, India.

PMID: 17584612
DOI: 10.1016/j.chembiol.2007.04.011

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acetylation
Animals
Anti-HIV Agents* / chemical synthesis
Anti-HIV Agents* / chemistry
Anti-HIV Agents* / pharmacology
Cell Cycle Proteins / antagonists & inhibitors*
Cell Cycle Proteins / genetics
Cell Survival / drug effects
Chromatin / genetics
Down-Regulation
Enzyme Inhibitors* / chemical synthesis
Enzyme Inhibitors* / chemistry
Enzyme Inhibitors* / pharmacology
Gene Expression / drug effects*
HIV-1* / drug effects
HIV-1* / genetics
HIV-1* / physiology
HeLa Cells
Histone Acetyltransferases / antagonists & inhibitors*
Histone Acetyltransferases / genetics
Histones / genetics
Humans
Models, Molecular
Molecular Structure
T-Lymphocytes / virology
Terpenes* / chemical synthesis
Terpenes* / chemistry
Terpenes* / pharmacology
Transcription Factors / antagonists & inhibitors*
Transcription Factors / genetics
Transcription, Genetic
Tumor Suppressor Protein p53 / metabolism
Up-Regulation
Virus Replication / drug effects*
p300-CBP Transcription Factors

Substances

Anti-HIV Agents
Cell Cycle Proteins
Chromatin
Enzyme Inhibitors
Histones
Terpenes
Transcription Factors
Tumor Suppressor Protein p53
Histone Acetyltransferases
p300-CBP Transcription Factors
p300-CBP-associated factor
garcinol

Associated data

GEO/GSE7818