Differential regulation of PML-RARα stability by the ubiquitin ligases SIAH1/SIAH2 and TRIAD1.
The ubiquitin proteasome system plays an important role in normal and malignant hematopoiesis and relies on the concerted action of three enzyme families. The E2 ubiquitin conjugase UBCH8 (ubiquitin conjugating enzyme [human] 8) cooperates with the E3 ubiquitin ligases SIAH1 and SIAH2 (seven in absentia homolog 1/2) to mediate the proteasomal degradation of oncoproteins. One such protein is the leukemia fusion protein PML-RARα (promyelocytic leukemia-retinoic acid receptorα) that is associated with acute promyelocytic leukemia. A limited number of UBCH8 interaction partners that participate in the UBCH8-dependent depletion of cancer-relevant proteins are known. We report here that TRIAD1 (two RING fingers and DRIL [double RING finger linked] 1), an E3 ubiquitin ligase relevant for the clonogenic growth of myloid progenitors, binds UBCH8 as well as PML-RARα. Moreover, there is concurrent induction of TRIAD1 and UBCH8 upon combinatorial treatment of acute promyelocytic leukemia cells with the pro-apoptotic epigenetic modulator valproic acid and the differentiation inducing agent all-trans retinoic acid. However, in sharp contrast to SIAH1/SIAH2 and UBCH8, TRIAD1 binding to PML-RARα has no effect on its turnover. In summary, our data exclude TRIAD1 as crucial regulator of the leukemic determinant PML-RARα, but highlight the prominence of the UBCH8/SIAH axis in PML-RARα degradation.
Institute of Biochemistry and Biophysics, Center for Molecular Biomedicine (CMB), Department of Biochemistry, University of Jena, Jena, Germany. kristin.pietschmann@googlemail.com
Kristin
K
Pietschmann
Marc
M
Buchwald
Sylvia
S
Müller
Shirley K
SK
Knauer
Manfred
M
Kögl
Thorsten
T
Heinzel
Oliver H
OH
Krämer
D002460:Cell Line; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000378:metabolism*; D015514:Oncogene Proteins, Fusion / Q000378:metabolism*; D014162:Transfection; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D000098563:Seven in Absentia Proteins
D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; C506696:ARIH2 protein, human; D044767:Ubiquitin-Protein Ligases; D000098563:Seven in Absentia Proteins