Mitochondrial Hep27 is a c-Myb target gene that inhibits Mdm2 and stabilizes p53.
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.
Deisenroth
Chad
C
University of North Carolina at Chapel Hill, Lineberger Comprehensive Cancer Center, School of Medicine, Chapel Hill, NC, USA.
Thorner
Aaron R
AR
Enomoto
Takeharu
T
Perou
Charles M
CM
Zhang
Yanping
Y
D000429:Alcohol Oxidoreductases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism; D000074409:Carbonyl Reductase (NADPH); D002460:Cell Line; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D005260:Female; D020570:Genes, myb; D006801:Humans; D066298:In Vitro Techniques; D016253:Microscopy, Immunoelectron; D008928:Mitochondria / Q000378:metabolism; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D011485:Protein Binding; D055550:Protein Stability; D000090063:Proto-Oncogene Mas; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D011960:Receptors, Estrogen / Q000378:metabolism; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
C000715470:MAS1 protein, human; D009687:Nuclear Proteins; D000090063:Proto-Oncogene Mas; D034741:RNA, Small Interfering; D011960:Receptors, Estrogen; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D000429:Alcohol Oxidoreductases; D000074409:Carbonyl Reductase (NADPH); C095961:DHRS2 protein, human; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2