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Abstract
The ever-expanding knowledge of the role of p53 in cellular metabolism, apoptosis, and cell cycle control has led to increasing interest in defining the stress response pathways that regulate Mdm2. In an effort to identify novel Mdm2 binding partners, we performed a large-scale immunoprecipitation of Mdm2 in the osteosarcoma U2OS cell line. One significant binding protein identified was Hep27, a member of the short-chain alcohol dehydrogenase/reductase (SDR) family of enzymes. Here, we demonstrate that the Hep27 preprotein contains an N-terminal mitochondrial targeting signal that is cleaved following mitochondrial import, resulting in mitochondrial matrix accumulation of mature Hep27. A fraction of the mitochondrial Hep27 translocates to the nucleus, where it binds to Mdm2 in the central domain, resulting in the attenuation of Mdm2-mediated p53 degradation. In addition, Hep27 is regulated at the transcriptional level by the proto-oncogene c-Myb and is required for c-Myb-induced p53 stabilization. Breast cancer gene expression analysis correlated estrogen receptor (ER) status with Hep27 expression and p53 function, providing a potential in vivo link between estrogen receptor signaling and p53 activity. Our data demonstrate a unique c-Myb-Hep27-Mdm2-p53 mitochondria-to-nucleus signaling pathway that may have functional significance for ER-positive breast cancers.
Supplemental material for this article may be found at http://mcb.asm.org/.
We thank Mikael Lindstrom, Koji Itahana, Everardo Macias, and Aiwen Jin for their helpful advice and technical assistance. Scott Ness generously provided c-Myb adenovirus for initial experiments.
Y.Z. is a recipient of a Career Award in Biomedical Science from the Burroughs Wellcome Fund, Howard Temin Award from the National Cancer Institute, and Scholar Award from the Leukemia & Lymphoma Society. This study was supported by grants from the NIH and the American Cancer Society to Y.Z. and by an NCI Breast SPORE grant and support from the Breast Cancer Research Foundation to C.M.P.