Epidermal growth factor up-regulates the transcription of mouse lon homology ATP-dependent protease through extracellular signal-regulated protein kinase- and phosphatidylinositol-3-kinase-dependent pathways.
Epidermal growth factor (EGF) induces tumorigenic transformation of mouse epidermal cells (JB6 P(+)). We cloned a full-length EGF-responsive cDNA in JB6P(+) cells; EGF up-regulated mRNA expression of this gene 5- to 6-fold. The deduced amino acid sequence of this cDNA exhibited 84 and 96% homology with human and rat Lon homology ATP-dependent protease, respectively, and all conserved domains of Lon, such as ATPase/protease domains, are present in the mouse gene, indicating that this gene is mouse Lon. EGF increased the transcriptional rate without affecting the mRNA stability of m-Lon. The level of m-Lon in irreversibly transformed mouse epidermal cells (JB7) was 3.4-fold higher than that in parental JB6 P(+) cells. Similarly, human mammary epithelial cells overexpressing the proto-oncogene ErbB2 expressed significantly higher levels of Lon than normal mammary epithelial cells. EGF failed to regulate Lon expression in ERK-deficient JB6 P(-) cells or cells that expressed the dominant-negative p85 P13-K regulatory unit. Furthermore, selective chemical blockers for MEK1 and P13-K (PD98059 and LY294002) inhibited EGF-mediated induction. Mitochondria-localized Lon protease plays a critical role in the regulation of mitochondrial gene expression and genome integrity. Disruption of mitochondrial homeostasis is a general characteristic of tumorigenic transformation. Thus, the role of Lon in tumor promotion warrants further study.
Zhu
Yunfeng
Y
Department of Microbiology, Immunology, and Cell Biology, West Virginia University School of Medicine, Morgantown 26506, USA.
Wang
Mei
M
Lin
Hong
H
Huang
Chuanshu
C
Shi
Xianglin
X
Luo
Jia
J
D049069:ATP-Dependent Proteases; D000595:Amino Acid Sequence; D000818:Animals; D001940:Breast / Q000166:cytology; D002460:Cell Line; D002461:Cell Line, Transformed; D002471:Cell Transformation, Neoplastic; D003001:Cloning, Molecular; D017124:Conserved Sequence; D000078404:Epidermal Cells; D004815:Epidermal Growth Factor / Q000235:genetics / Q000494:pharmacology*; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D006360:Heat-Shock Proteins / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D020935:MAP Kinase Signaling System; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008969:Molecular Sequence Data; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000090063:Proto-Oncogene Mas; D012333:RNA, Messenger / Q000378:metabolism; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D012697:Serine Endopeptidases / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology; D015533:Transcriptional Activation; D014170:Transformation, Genetic; D015854:Up-Regulation
D049069:ATP-Dependent Proteases; D004815:Epidermal Growth Factor; D006360:Heat-Shock Proteins; D020928:Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D000090063:Proto-Oncogene Mas; D012333:RNA, Messenger; D012697:Serine Endopeptidases; C000715470:MAS1 protein, human