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Chfr is linked to tumour metastasis through the downregulation of HDAC1
Oh, Young Mi,Kwon, Young Eun,Kim, Joo Mi,Bae, Sung Jun,Lee, Bo Keun,Yoo, Soon Ji,Chung, Chin Ha,Deshaies, Raymond J.,Seol, Jae Hong Nature Publishing Group 2009 Nature cell biology Vol.11 No.3
Chfr is a ubiquitin ligase that functions in the mitotic checkpoint by delaying entry into metaphase in response to mitotic stress. It has been suggested that Chfr is a tumour suppressor as Chfr is frequently silenced in human cancers. To better understand how Chfr activity relates to cell-cycle progression and tumorigenesis, we sought to identify Chfr-interacting proteins using affinity purification combined with mass spectrometry. Histone deacetylase 1 (HDAC1), which represses transcription by deacetylating histones, was newly isolated as a Chfr-interacting protein. Chfr binds and downregulates HDAC1 by inducing its polyubiquitylation, both in vitro and in vivo. Ectopic expression of Chfr in cancer cells that normally do not express it results in downregulation of HDAC1, leading to upregulation of the Cdk inhibitor p21<SUP>CIP1/WAF1</SUP> and the metastasis suppressors KAI1 and E-cadherin. Coincident with these changes, cells arrest in the G1 phase of the cell cycle and become less invasive. Collectively, our data suggest that Chfr functions as a tumour suppressor by regulating HDAC1.
Cand1 Promotes Assembly of New SCF Complexes through Dynamic Exchange of F Box Proteins
Pierce, Nathan W.,Lee, J.,Liu, X.,Sweredoski, Michael J.,Graham, Robert L.J.,Larimore, Elizabeth A.,Rome, M.,Zheng, N.,Clurman, Bruce E.,Hess, S.,Shan, S.o.,Deshaies, Raymond J. Cell Press ; MIT Press 2013 Cell Vol.153 No.1
The modular SCF (Skp1, cullin, and F box) ubiquitin ligases feature a large family of F box protein substrate receptors that enable recognition of diverse targets. However, how the repertoire of SCF complexes is sustained remains unclear. Real-time measurements of formation and disassembly indicate that SCF<SUP>Fbxw7</SUP> is extraordinarily stable, but, in the Nedd8-deconjugated state, the cullin-binding protein Cand1 augments its dissociation by one-million-fold. Binding and ubiquitylation assays show that Cand1 is a protein exchange factor that accelerates the rate at which Cul1-Rbx1 equilibrates with multiple F box protein-Skp1 modules. Depletion of Cand1 from cells impedes recruitment of new F box proteins to pre-existing Cul1 and profoundly alters the cellular landscape of SCF complexes. We suggest that catalyzed protein exchange may be a general feature of dynamic macromolecular machines and propose a hypothesis for how substrates, Nedd8, and Cand1 collaborate to regulate the cellular repertoire of SCF complexes.
Van Nguyen, T.,Lee, J.,Sweredoski, Michael J.,Yang, S.J.,Jeon, S.J.,Harrison, Joseph S.,Yim, J.H.,Lee, S.,Handa, H.,Kuhlman, B.,Jeong, J.S.,Reitsma, Justin M.,Park, C.S.,Hess, S.,Deshaies, Raymond J. Cell Press 2016 Molecular cell Vol.61 No.6
<P>Cereblon (CRBN), a substrate receptor for the cullin-RING ubiquitin ligase 4 (CRL4) complex, is a direct protein target for thalidomide teratogenicity and antitumor activity of immunomodulatory drugs (IMiDs). Here we report that glutamine synthetase (GS) is an endogenous substrate of CRL4(CRBN). Upon exposing cells to high glutamine concentration, GS is acetylated at lysines 11 and 14, yielding a degron that is necessary and sufficient for binding and ubiquitylation by CRL4 CRBN and degradation by the proteasome. Binding of acetylated degron peptides to CRBN depends on an intact thalidomide-binding pocket but is not competitive with IMiDs. These findings reveal a feedback loop involving CRL4 CRBN that adjusts GS protein levels in response to glutamine and uncover a new function for lysine acetylation.</P>