TY  - JOUR
A1  - Sander, Bodo
A1  - Xu, Wenshan
A1  - Eilers, Martin
A1  - Popov, Nikita
A1  - Lorenz, Sonja
T1  - A conformational switch regulates the ubiquitin ligase HUWE1
JF  - eLife
N2  - The human ubiquitin ligase HUWE1 has key roles in tumorigenesis, yet it is unkown how its activity is regulated. We present the crystal structure of a C-terminal part of HUWE1, including the catalytic domain, and reveal an asymmetric auto-inhibited dimer. We show that HUWE1 dimerizes in solution and self-associates in cells, and that both occurs through the crystallographic dimer interface. We demonstrate that HUWE1 is inhibited in cells and that it can be activated by disruption of the dimer interface. We identify a conserved segment in HUWE1 that counteracts dimer formation by associating with the dimerization region intramolecularly. Our studies reveal, intriguingly, that the tumor suppressor p14ARF binds to this segment and may thus shift the conformational equilibrium of HUWE1 toward the inactive state. We propose a model, in which the activity of HUWE1 underlies conformational control in response to physiological cues—a mechanism that may be exploited for cancer therapy.
KW  - Medicine
KW  - Structural Biology
KW  - Molecular Biophysics
KW  - HUWE1
KW  - HECT Ligase
KW  - Ubiquitin
KW  - P14ARF
KW  - X-Ray Chrystallography
KW  - Enzyme Regulation
Y1  - 2017
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-171862
VL  - 6
ER  - 
TY  - JOUR
A1  - Yanku, Yifat
A1  - Bitman-Lotan, Eliya
A1  - Zohar, Yaniv
A1  - Kurant, Estee
A1  - Zilke, Norman
A1  - Eilers, Martin
A1  - Orian, Amir
T1  - Drosophila HUWE1 ubiquitin ligase regulates endoreplication and antagonizes JNK signaling during salivary gland development
JF  - Cells
N2  - The HECT-type ubiquitin ligase HECT, UBA and WWE Domain Containing 1, (HUWE1) regulates key cancer-related pathways, including the Myc oncogene. It affects cell proliferation, stress and immune signaling, mitochondria homeostasis, and cell death. HUWE1 is evolutionarily conserved from Caenorhabditis elegance to Drosophila melanogaster and Humans. Here, we report that the Drosophila ortholog, dHUWE1 (CG8184), is an essential gene whose loss results in embryonic lethality and whose tissue-specific disruption establishes its regulatory role in larval salivary gland development. dHUWE1 is essential for endoreplication of salivary gland cells and its knockdown results in the inability of these cells to replicate DNA. Remarkably, dHUWE1 is a survival factor that prevents premature activation of JNK signaling, thus preventing the disintegration of the salivary gland, which occurs physiologically during pupal stages. This function of dHUWE1 is general, as its inhibitory effect is observed also during eye development and at the organismal level. Epistatic studies revealed that the loss of dHUWE1 is compensated by dMyc proeitn expression or the loss of dmP53. dHUWE1 is therefore a conserved survival factor that regulates organ formation during Drosophila development.
KW  - HECT
KW  - HUWE1
KW  - ubiquitin
KW  - salivary gland
KW  - endoreplication
KW  - JNK
KW  - dMyc
KW  - dmP53
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-197630
SN  - 2073-4409
VL  - 7
IS  - 10
ER  - 
TY  - JOUR
A1  - Peter, Stefanie
A1  - Bultinck, Jennyfer
A1  - Myant, Kevin
A1  - Jaenicke, Laura A.
A1  - Walz, Susanne
A1  - Müller, Judith
A1  - Gmachl, Michael
A1  - Treu, Matthias
A1  - Boehmelt, Guido
A1  - Ade, Casten P.
A1  - Schmitz, Werner
A1  - Wiegering, Armin
A1  - Otto, Christoph
A1  - Popov, Nikita
A1  - Sansom, Owen
A1  - Kraut, Norbert
A1  - Eilers, Martin
T1  - H Tumor cell-specific inhibition of MYC function using small molecule inhibitors of the HUWE1 ubiquitin ligase
JF  - EMBO Molecular Medicine
N2  - Deregulated expression of MYC is a driver of colorectal carcinogenesis, necessitating novel strategies to inhibit MYC function. The ubiquitin ligase HUWE1 (HECTH9, ARF-BP1, MULE) associates with both MYC and the MYC-associated protein MIZ1. We show here that HUWE1 is required for growth of colorectal cancer cells in culture and in orthotopic xenograft models. Using high-throughput screening, we identify small molecule inhibitors of HUWE1, which inhibit MYC-dependent transactivation in colorectal cancer cells, but not in stem and normal colon epithelial cells. Inhibition of HUWE1 stabilizes MIZ1. MIZ1 globally accumulates on MYC target genes and contributes to repression of MYC-activated target genes upon HUWE1 inhibition. Our data show that transcriptional activation by MYC in colon cancer cells requires the continuous degradation of MIZ1 and identify a novel principle that allows for inhibition of MYC function in tumor cells.
KW  - colorectal cancer
KW  - HUWE1
KW  - MIZ1
KW  - MYC
KW  - ubiquitination
KW  - cancer
KW  - digestive system
KW  - pharmacology
KW  - drug discovery
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-118132
SN  - 1757-4684
VL  - 6
IS  - 12
ER  -