Our long-term goal is to prevent liver cancer by eliminating dietary aflatoxin and human exposure to this mycotoxin in food. In past research, we made significant progress towards this long-term goal and accomplished two short-term goals. (1) We identified key components in the genetic switch that activate aflatoxin gene expression and developed a comprehensive model that predicts the detailed mechanisms by which the switch regulates the timing and level of aflatoxin synthesis. (2) We identified several fungal and plant metabolites that block aflatoxin accumulation and gene expression. In the next phase of this research, we will analyze two key components of the switch mechanism in sufficient detail to identify specific steps that are susceptible to control. Using this information, we will continue to identify and test promising natural plant and fungal compounds that block aflatoxin synthesis. This research approach will allow us to confirm or modify key steps in the regulatory model and will fill a critical knowledge gap in our understanding of aflatoxin synthesis specifically and in control of complex gene clusters in general. This approach will also assist efforts to formulate and apply effective strategies to block aflatoxin synthesis on susceptible crops. Based on our model of the genetic switch, we present two central hypotheses: 1) active CRE1bp complexes recruit proteins necessary for initiation of aflatoxin gene expression (AflR and HAT);2) the timing and level of aflatoxin gene activation is in part controlled by the initiation and spread of histone H4 acetylation in the aflatoxin gene cluster. To address these hypotheses, we propose to accomplish two Specific Aims. 1. Analyze the role of CRE1bp in aflatoxin gene activation. 2. Analyze the role of histone H4 acetylation in aflatoxin gene activation. As part of the proposed work for each specific aim, we will identify new inhibitors of aflatoxin synthesis and determine the specific mechanisms by which these and previously identified inhibitors block aflatoxin synthesis. Our work will allow us to effectively control aflatoxin synthesis on food and feed crops - this outcome will have a large positive impact on human health by providing one practical strategy to reduce liver cancer incidence.

Public Health Relevance

As part of the proposed work, we will identify new inhibitors of aflatoxin synthesis and determine the specific mechanisms by which these and previously identified inhibitors block aflatoxin synthesis. Our work will allow us to effectively control aflatoxin synthesis on food and feed crops. This outcome will have a large positive impact on human health by providing one practical strategy to reduce liver cancer incidence.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA052003-21
Application #
8255601
Study Section
Cancer Etiology Study Section (CE)
Program Officer
Johnson, Ronald L
Project Start
1991-01-01
Project End
2013-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
21
Fiscal Year
2012
Total Cost
$206,479
Indirect Cost
$64,753
Name
Michigan State University
Department
Nutrition
Type
Schools of Earth Sciences/Natur
DUNS #
193247145
City
East Lansing
State
MI
Country
United States
Zip Code
48824
Linz, John E; Wee, Josephine; Roze, Ludmila V (2014) Aspergillus parasiticus SU-1 genome sequence, predicted chromosome structure, and comparative gene expression under aflatoxin-inducing conditions: evidence that differential expression contributes to species phenotype. Eukaryot Cell 13:1113-23
Hong, Sung-Yong; Roze, Ludmila V; Wee, Josephine et al. (2013) Evidence that a transcription factor regulatory network coordinates oxidative stress response and secondary metabolism in aspergilli. Microbiologyopen 2:144-60
Linz, John E; Chanda, Anindya; Hong, Sung-Yong et al. (2012) Proteomic and biochemical evidence support a role for transport vesicles and endosomes in stress response and secondary metabolism in aspergillus parasiticus. J Proteome Res 11:767-75
Roze, Ludmila V; Chanda, Anindya; Linz, John E (2011) Compartmentalization and molecular traffic in secondary metabolism: a new understanding of established cellular processes. Fungal Genet Biol 48:35-48
Roze, Ludmila V; Koptina, Anna V; Laivenieks, Maris et al. (2011) Willow volatiles influence growth, development, and secondary metabolism in Aspergillus parasiticus. Appl Microbiol Biotechnol 92:359-70
Chanda, Anindya; Roze, Ludmila V; Kang, Suil et al. (2009) A key role for vesicles in fungal secondary metabolism. Proc Natl Acad Sci U S A 106:19533-8
Chanda, Anindya; Roze, Ludmila V; Pastor, Alicia et al. (2009) Purification of a vesicle-vacuole fraction functionally linked to aflatoxin synthesis in Aspergillus parasiticus. J Microbiol Methods 78:28-33
Hong, Sung-Yong; Linz, John E (2009) Functional expression and sub-cellular localization of the early aflatoxin pathway enzyme Nor-1 in Aspergillus parasiticus. Mycol Res 113:591-601
Hong, Sung-Yong; Linz, John E (2008) Functional expression and subcellular localization of the aflatoxin pathway enzyme Ver-1 fused to enhanced green fluorescent protein. Appl Environ Microbiol 74:6385-96
Roze, Ludmila V; Arthur, Anna E; Hong, Sung-Yong et al. (2007) The initiation and pattern of spread of histone H4 acetylation parallel the order of transcriptional activation of genes in the aflatoxin cluster. Mol Microbiol 66:713-26

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