Identification of the KAI1 metastasis suppressor gene as a hypoxia target gene.
KAI1 is a metastasis suppressor gene known to inhibit cancer metastasis without affecting primary tumorigenicity. Although KAI1 expression has been reported to undergo transcriptional regulation, how its expression is up- or down-regulated by specific upstream signaling pathways has not been studied in detail. In this study, we characterized the regulatory elements within the 500bp upstream region of mouse KAI1 gene and identified a functional hypoxia-response element (HRE) within the promoter region. Hypoxia-dependent induction of KAI1 was directly mediated by hypoxia-inducible factor (HIF)-1alpha binding on the promoter, which subsequently caused increased recruitment of RNA polymerase II for transcriptional activation. The failure of HIF-1alpha recruitment to the KAI1 promoter was observed in Hif-1alpha knockout mouse embryonic fibroblasts. Furthermore, KAI1 protein synthesis was markedly increased in ischemic tissues, suggesting that KAI1 is a hypoxia target gene in vivo.
Kim
Bogyou
B
Department of Biological Sciences, Creative Research Initiatives Center for Chromatin Dynamics, Seoul National University, Seoul 151-742, South Korea.
Boo
Kyungjin
K
Lee
Jason S
JS
Kim
Keun Il
KI
Kim
Woo Ho
WH
Cho
Hyun-Jai
HJ
Park
Young-Bae
YB
Kim
Hyo-Soo
HS
Baek
Sung Hee
SH
D000818:Animals; D015687:Cell Hypoxia / Q000235:genetics; D002460:Cell Line; D006801:Humans; D000860:Hypoxia / Q000235:genetics* / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D051861:Kangai-1 Protein / Q000235:genetics*; D051379:Mice; D017202:Myocardial Ischemia / Q000235:genetics / Q000378:metabolism; D041681:NIH 3T3 Cells; D010100:Oxygen / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D020218:Response Elements; D015533:Transcriptional Activation
C497689:Cd82 antigen, mouse; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051861:Kangai-1 Protein; D010100:Oxygen