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Mechanism for ubiquitylation of the leukemia fusion proteins AML1‐ETO and PML‐RARα
Author(s) -
Krämer Oliver H.,
Müller Sylvia,
Buchwald Marc,
Reichardt Sigrid,
Heinzel Thorsten
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.06-8050com
Subject(s) - ubiquitin ligase , ubiquitin , proteasome , microbiology and biotechnology , mechanism (biology) , chromosomal translocation , leukemia , biology , histone deacetylase , histone , chemistry , cancer research , biochemistry , genetics , gene , philosophy , epistemology
The chromosomal translocation prod ucts AML1‐ETO and PML‐RARα contribute to the pathogenesis of leukemias. Here, we demonstrate that both AML1‐ETO and PML‐RARα are degraded by the ubiquitin‐proteasome system and that their turnover critically depends on the E2‐conjugase UbcH8 and the E3‐ligase SIAH‐1. Contrary to its role in HDAC2 degra dation, the E3‐ligase RLIM does not target AML1‐ETO and PML‐RARα for ubiquitin‐dependent elimination. RLIM rather is a substrate of SIAH‐1, which indicates that these E3‐ligases operate in a hierarchical order. Remarkably, proteasomal degradation of leukemia fusion proteins, in addition to the block of histone deacetylase (HDAC) enzymatic activity is a conse quence of HDAC‐inhibitor treatment. The former re quires the induction of UbcH8 expression and each of these processes might be beneficial for leukemia treat ment. Our observations shed light on the mechanism determining the interplay between E2‐conjugases, E3‐ ligases, and their substrates and suggest a strategy for utilizing the ubiquitylation machinery in a therapeutic setting.—Krämer, O. H., Müller, S., Buchwald, M., Reichardt, S., Heinzel, T. Mechanism for ubiquitylation of the leukemia fusion proteins AML1‐ETO and PML‐ RARa. FASEB J . 22, 1369–1379 (2008)