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Molecular and Cellular Biology, February 2005, p. 1089-1099, Vol. 25, No. 3
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.3.1089-1099.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Nuclear Oncoprotein Prothymosin {alpha} Is a Partner of Keap1: Implications for Expression of Oxidative Stress-Protecting Genes

Ruben N. Karapetian,1 Alexandra G. Evstafieva,1 Irina S. Abaeva,1 Nina V. Chichkova,1 Grigoriy S. Filonov,1 Yuri P. Rubtsov,1 Elena A. Sukhacheva,2 Sergey V. Melnikov,1 Ulrich Schneider,3 Erich E. Wanker,4 and Andrey B. Vartapetian1*

Belozersky Institute of Physico-Chemical Biology, Moscow State University,1 Shemiakin and Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia,2 Max Planck Institute for Molecular Genetics,3 Max Delbrueck Center for Molecular Medicine, Berlin, Germany4

Received 8 June 2004/ Returned for modification 9 August 2004/ Accepted 25 October 2004

Animal cells counteract oxidative stress and electrophilic attack through coordinated expression of a set of detoxifying and antioxidant enzyme genes mediated by transcription factor Nrf2. In unstressed cells, Nrf2 appears to be sequestered in the cytoplasm via association with an inhibitor protein, Keap1. Here, by using the yeast two-hybrid screen, human Keap1 has been identified as a partner of the nuclear protein prothymosin {alpha}. The in vivo and in vitro data indicated that the prothymosin {alpha}-Keap1 interaction is direct, highly specific, and functionally relevant. Furthermore, we showed that Keap1 is a nuclear-cytoplasmic shuttling protein equipped with a nuclear export signal that is important for its inhibitory action. Prothymosin {alpha} was able to liberate Nrf2 from the Nrf2-Keap1 inhibitory complex in vitro through competition with Nrf2 for binding to the same domain of Keap1. In vivo, the level of Nrf2-dependent transcription was correlated with the intracellular level of prothymosin {alpha} by using prothymosin {alpha} overproduction and mRNA interference approaches. Our data attribute to prothymosin {alpha} the role of intranuclear dissociator of the Nrf2-Keap1 complex, thus revealing a novel function for prothymosin {alpha} and adding a new dimension to the molecular mechanisms underlying expression of oxidative stress-protecting genes.

* Corresponding author. Mailing address: Belozersky Institute of Physico-Chemical Biology, Moscow State University, Moscow 119992, Russia. Phone: (7) (095) 939-4125. Fax: (7) (095) 939-3181. E-mail: varta{at}genebee.msu.su.

Molecular and Cellular Biology, February 2005, p. 1089-1099, Vol. 25, No. 3
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.3.1089-1099.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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