Post-transcriptional up-regulation of ADAM17 upon epidermal growth factor receptor activation and in breast tumors.
ADAM17 is a transmembrane metalloprotease involved in the proteolytic release of the extracellular domain of many cell surface molecules, a process known as ectodomain shedding. Despite its likely participation in tumor progression and its current consideration as a therapeutic target, very little is known about the regulation of the expression of ADAM17. Here we show that long term treatment with epidermal growth factor (EGF) leads to a marked increase in the levels of ADAM17. EGF receptor activation does not affect the levels of the mRNA that encodes for, or the rate of synthesis of, ADAM17 but increases its half-life. The effect of EGF is biologically relevant because it increases the shedding of several substrates of ADAM17, including the desmosomal cadherin Dsg-2. Analysis of protein and mRNA levels in mammary tumor samples shows that in vivo the levels of ADAM17 can also be controlled post-transcriptionally. Finally, we show that both the shed extracellular domains of Dsg-2 and ADAM17 are frequently expressed in tumors, further supporting the participation of the metalloprotease in malignant progression.
Santiago-Josefat
Belén
B
Medical Oncology Research Program, Vall d'Hebron University Hospital Research Institute, Passeig Vall d'Hebron 119-129, 08035 Barcelona, Spain.
Esselens
Cary
C
Bech-Serra
Joan Josep
JJ
Arribas
Joaquín
J
D051722:ADAM Proteins / Q000378:metabolism*; D000072198:ADAM17 Protein; D019921:Biotinylation; D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D051301:Desmoglein 2 / Q000378:metabolism; D018450:Disease Progression; D004815:Epidermal Growth Factor / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D012323:RNA Processing, Post-Transcriptional; D011994:Recombinant Proteins; D013997:Time Factors; D015854:Up-Regulation
D016895:Culture Media, Serum-Free; C495314:DSG2 protein, human; D051301:Desmoglein 2; D011994:Recombinant Proteins; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human