TY - JOUR
T1 - Toxicogenomics of endoplasmic reticulum stress inducer tunicamycin in the small intestine and liver of Nrf2 knockout and C57BL/6J mice
AU - Nair, Sujit
AU - Xu, Changjiang
AU - Shen, Guoxiang
AU - Hebbar, Vidya
AU - Gopalakrishnan, Avantika
AU - Hu, Rong
AU - Jain, Mohit Raja
AU - Liew, Celine
AU - Chan, Jefferson Y.
AU - Kong, Ah Ng Tony
N1 - Funding Information:
The authors are deeply grateful to Mr. Curtis Krier at the Cancer Institute of New Jersey (CINJ) Core Expression Array Facility for his expert assistance with the microarray analyses. The authors are also deeply indebted to Ms. Donna Wilson of the Keck Center for Collaborative Neuroscience, Rutgers University as well as the staff of the Human Genetics Institute of New Jersey at Rutgers University for their great expertise and help with the quantitative real-time PCR analyses. This work was supported in part by NIH grant R01-094828.
PY - 2007/1/10
Y1 - 2007/1/10
N2 - This objective of this study was to investigate the toxicogenomics and the spatial regulation of global gene expression profiles elicited by endoplasmic reticulum (ER) stress inducer tunicamycin (TM) in mouse small intestine and liver as well as to identify TM-modulated nuclear factor-E2-related factor 2 (Nrf2)-dependent genes. Gene expression profiles were analyzed using 45,000 Affymetrix mouse genome 430 2.0 array and GeneSpring 7.2 software. Microarray results were validated by quantitative real-time reverse transcription-PCR analyses. Clusters of genes that were either induced or suppressed more than two-fold by TM treatment compared with vehicle in C57BL/6J/Nrf2 (-/-; knockout) and C57BL/6J Nrf2 (+/+; wildtype) mice genotypes were identified. Amongst these, in small intestine and liver, 1291 and 750 genes, respectively, were identified as Nrf2-dependent and upregulated, and 1370 and 943 genes, respectively, as Nrf2-dependent and downregulated. Based on their biological functions, these genes can be categorized into molecular chaperones and heat shock proteins, ubiquitination/proteolysis, apoptosis/cell cycle, electron transport, detoxification, cell growth/differentiation, signaling molecules/interacting partners, kinases and phosphatases, transport, biosynthesis/metabolism, nuclear assembly and processing, and genes related to calcium and glucose homeostasis. Phase II detoxification/antioxidant genes as well as putative interacting partners of Nrf2 such as nuclear corepressors and coactivators, were also identified as Nrf2-dependent genes. The identification of TM-regulated and Nrf2-dependent genes in the unfolded protein response to ER stress not only provides potential novel insights into the gestalt biological effects of TM on the toxicogenomics and spatial regulation of global gene expression profiles in cancer pharmacology and toxicology, but also points to the pivotal role of Nrf2 in these biological processes.
AB - This objective of this study was to investigate the toxicogenomics and the spatial regulation of global gene expression profiles elicited by endoplasmic reticulum (ER) stress inducer tunicamycin (TM) in mouse small intestine and liver as well as to identify TM-modulated nuclear factor-E2-related factor 2 (Nrf2)-dependent genes. Gene expression profiles were analyzed using 45,000 Affymetrix mouse genome 430 2.0 array and GeneSpring 7.2 software. Microarray results were validated by quantitative real-time reverse transcription-PCR analyses. Clusters of genes that were either induced or suppressed more than two-fold by TM treatment compared with vehicle in C57BL/6J/Nrf2 (-/-; knockout) and C57BL/6J Nrf2 (+/+; wildtype) mice genotypes were identified. Amongst these, in small intestine and liver, 1291 and 750 genes, respectively, were identified as Nrf2-dependent and upregulated, and 1370 and 943 genes, respectively, as Nrf2-dependent and downregulated. Based on their biological functions, these genes can be categorized into molecular chaperones and heat shock proteins, ubiquitination/proteolysis, apoptosis/cell cycle, electron transport, detoxification, cell growth/differentiation, signaling molecules/interacting partners, kinases and phosphatases, transport, biosynthesis/metabolism, nuclear assembly and processing, and genes related to calcium and glucose homeostasis. Phase II detoxification/antioxidant genes as well as putative interacting partners of Nrf2 such as nuclear corepressors and coactivators, were also identified as Nrf2-dependent genes. The identification of TM-regulated and Nrf2-dependent genes in the unfolded protein response to ER stress not only provides potential novel insights into the gestalt biological effects of TM on the toxicogenomics and spatial regulation of global gene expression profiles in cancer pharmacology and toxicology, but also points to the pivotal role of Nrf2 in these biological processes.
KW - Endoplasmic reticulum stress
KW - Global gene expression profiles
KW - Microarray
KW - Nuclear factor-E2-related factor 2
KW - Tunicamycin
UR - http://www.scopus.com/inward/record.url?scp=33845523674&partnerID=8YFLogxK
U2 - 10.1016/j.toxlet.2006.10.012
DO - 10.1016/j.toxlet.2006.10.012
M3 - Article
C2 - 17127020
AN - SCOPUS:33845523674
SN - 0378-4274
VL - 168
SP - 21
EP - 39
JO - Toxicology Letters
JF - Toxicology Letters
IS - 1
ER -
