TY - JOUR
T1 - Regulation of the Sre1 hypoxic transcription factor by oxygen-dependent control of DNA binding
AU - Lee, Chih Yung S.
AU - Yeh, Tzu Lan
AU - Hughes, Bridget T.
AU - Espenshade, Peter J.
N1 - Funding Information:
We thank Espenshade and Amzel Lab members for experimental suggestions and for reviewing the paper. We thank Wayne Lai and Ling-Chu Hung in the Department of Pathology at UT-Southwestern Medical Center at Dallas for help in generating monoclonal antibody to Sre1. We thank Takashi Toda (London Research Institute) and Dieter Wolf (Sanford-Burnham Medical Research Institute) for kindly providing yeast strains. This study was supported by a grant from the National Institutes of Health to P.J.E. (HL-077588). C.-Y.S.L. and B.T.H. are recipients of American Heart Association Predoctoral Fellowships, and P.J.E. is an Established Investigator of the American Heart Association.
PY - 2011/10/21
Y1 - 2011/10/21
N2 - Regulation of gene expression plays an integral role in adaptation of cells to hypoxic stress. In mammals, prolyl hydroxylases control levels of the central transcription factor hypoxia inducible factor (HIF) through regulation of HIFα subunit stability. Here, we report that the hydroxylase Ofd1 regulates the Sre1 hypoxic transcription factor in fission yeast by controlling DNA binding. Prolyl hydroxylases require oxygen as a substrate, and the activity of Ofd1 regulates Sre1-dependent transcription. In the presence of oxygen, Ofd1 binds the Sre1 N-terminal transcription factor domain (Sre1N) and inhibits Sre1-dependent transcription by blocking DNA binding. In the absence of oxygen, the inhibitor Nro1 binds Ofd1, thereby releasing Sre1N and leading to activation of genes required for hypoxic growth. In contrast to the HIF system, where proline hydroxylation is essential for regulation, Ofd1 inhibition of Sre1N does not require hydroxylation and, thus, defines a new mechanism for hypoxic gene regulation.
AB - Regulation of gene expression plays an integral role in adaptation of cells to hypoxic stress. In mammals, prolyl hydroxylases control levels of the central transcription factor hypoxia inducible factor (HIF) through regulation of HIFα subunit stability. Here, we report that the hydroxylase Ofd1 regulates the Sre1 hypoxic transcription factor in fission yeast by controlling DNA binding. Prolyl hydroxylases require oxygen as a substrate, and the activity of Ofd1 regulates Sre1-dependent transcription. In the presence of oxygen, Ofd1 binds the Sre1 N-terminal transcription factor domain (Sre1N) and inhibits Sre1-dependent transcription by blocking DNA binding. In the absence of oxygen, the inhibitor Nro1 binds Ofd1, thereby releasing Sre1N and leading to activation of genes required for hypoxic growth. In contrast to the HIF system, where proline hydroxylation is essential for regulation, Ofd1 inhibition of Sre1N does not require hydroxylation and, thus, defines a new mechanism for hypoxic gene regulation.
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U2 - 10.1016/j.molcel.2011.08.031
DO - 10.1016/j.molcel.2011.08.031
M3 - Article
C2 - 22017871
AN - SCOPUS:82455172129
SN - 1097-2765
VL - 44
SP - 225
EP - 234
JO - Molecular cell
JF - Molecular cell
IS - 2
ER -