The testis-specific USP26 is a deubiquitinating enzyme of the ubiquitin ligase Mdm2.
Murine double minute-2 (Mdm2) is one of the E3-ligases of the androgen receptor besides being the major regulator of the p53 tumor suppressor. The testis-specific USP26 was demonstrated to regulate the androgen receptor. In the present study we examined possible association between the deubiquitinating enzyme - ubiquitin specific protease 26 (USP26), and the oncoprotein E3 ligase - (Mdm-2). We analyzed the half-life time of USP26 in HEK293 cells. In a cell-free system we asked whether USP26 can be ubiquitinated by HeLa extract. In co-transfection experiments we expressed Mdm2 along with different constructs of USP26 in order to examine possible regulation of Mdm2 by USP26. We found that USP26 binds to Mdm2 through its coiled-coiled C-terminal domain. USP26 deubiquitinates Mdm2 and stabilizes it. The physiological significance of the findings is still not fully understood. The interaction between USP26 and Mdm2, and the subsequent deubiquitination of Mdm2, serves, most probably to regulate Mdm2. Future therapeutic modalities that interfere with the association between USP26 and Mdm2 will be used to destabilize the ligase in malignancies where it is upregulated.
Department of Obstetrics and Gynecology, IVF Unit, Lady Davis Carmel Medical Center, Haifa, Israel. Electronic address: lahav_shirly@clalit.org.il.
Shirly
S
Lahav-Baratz
Technion Integrative Cancer Center, The Rappaport Faculty of Medicine and Research Institute, Technion - Israel Institute of Technology, Haifa, Israel.
Yelena
Y
Kravtsova-Ivantsiv
Department of Urology, Rabin Medical Center - Beilinson Hospital, Petach Tikva and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
Shay
S
Golan
Technion Integrative Cancer Center, The Rappaport Faculty of Medicine and Research Institute, Technion - Israel Institute of Technology, Haifa, Israel.
Aaron
A
Ciechanover
D001665:Binding Sites; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D000072017:Deubiquitinating Enzymes / Q000378:metabolism*; D004789:Enzyme Activation; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D009928:Organ Specificity / Q000502:physiology; D011485:Protein Binding; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D013379:Substrate Specificity; D013737:Testis / Q000201:enzymology*; D025801:Ubiquitin / Q000378:metabolism*
C501866:USP26 protein, human; D025801:Ubiquitin; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D000072017:Deubiquitinating Enzymes; D003546:Cysteine Endopeptidases
DUB; Male infertility; Mdm2; Spermatozoa; USP26