scholarly journals A Unique Protection Signal in Cubitus interruptus Prevents Its Complete Proteasomal Degradation

2008 ◽  
Vol 28 (18) ◽  
pp. 5555-5568 ◽  
Author(s):  
Yifei Wang ◽  
Mary Ann Price
Keyword(s):  
Zinc Finger ◽  
Limited Proteolysis ◽  
Cubitus Interruptus ◽  
Ubiquitin Proteasome Pathway ◽  
Amino Acid Region ◽  
C Terminus ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway ◽  
Zinc Finger Region ◽  
Acid Region

ABSTRACT The limited proteolysis of Cubitus interruptus (Ci), the transcription factor for the developmentally and medically important Hedgehog (Hh) signaling pathway, triggers a critical switch between transcriptional repressor and activator forms. Ci repressor is formed when the C terminus of full-length Ci is degraded by the ubiquitin-proteasome pathway, an unusual reaction since the proteasome typically completely degrades its substrates. We show that several regions of Ci are required for generation of the repressor form: the zinc finger DNA binding domain, a single lysine residue (K750) near the degradation end point, and a 163-amino-acid region at the C terminus. Unlike other proteins that are partially degraded by the proteasome, dimerization is not a key feature of Ci processing. Using a pulse-chase assay in cultured Drosophila cells, we distinguish between regions required for initiation of degradation and those required for the protection of the Ci N terminus from degradation. We present a model whereby the zinc finger region and K750 together form a unique protection signal that prevents the complete degradation of Ci by the proteasome.

scholarly journals A Conserved Protein with AN1 Zinc Finger and Ubiquitin-like Domains Modulates Cdc48 (p97) Function in the Ubiquitin-Proteasome Pathway

2013 ◽  
Vol 288 (47) ◽  
pp. 33682-33696 ◽  
Author(s):  
Bebiana Sá-Moura ◽  
Minoru Funakoshi ◽  
Robert J. Tomko ◽  
R. Jürgen Dohmen ◽  
Zhiping Wu ◽  
...  
Keyword(s):  
Zinc Finger ◽  
Ubiquitin Proteasome Pathway ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway

scholarly journals Turning Off Estrogen Receptor β-Mediated Transcription Requires Estrogen-Dependent Receptor Proteolysis

2006 ◽  
Vol 26 (21) ◽  
pp. 7966-7976 ◽  
Author(s):  
Yukiyo Tateishi ◽  
Raku Sonoo ◽  
Yu-ichi Sekiya ◽  
Nanae Sunahara ◽  
Miwako Kawano ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Active Form ◽  
Estrogen Receptor Β ◽  
Interacting Protein ◽  
Amino Acid Region ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway ◽  
Interfering Rna ◽  
Shed Light ◽  
Acid Region

ABSTRACT Recent studies have shed light on the ligand-dependent transactivation mechanisms of nuclear receptors (NRs). When the ligand dose is reduced, the transcriptional activity of NRs should be downregulated. Here we show that a ubiquitin-proteasome pathway plays a key role in turning off transcription mediated by estrogen receptor β (ERβ). ERβ shows estrogen-dependent proteolysis, and its degradation is regulated by two regions in the receptor. The N-terminal 37-amino acid-region is necessary for the recruitment of the ubiquitin ligase, i.e., the carboxyl terminus of HSC70-interacting protein (CHIP), to degrade ERβ. In contrast, the C-terminal F domain protects ligand-unbound ERβ from proteolysis to abrogate proteasome association. Suppression of CHIP by interfering RNA inhibited this switching off of receptor-mediated transcription when the ligand dose was reduced. Our results suggest that after ligand withdrawal, the active form of the NR is selectively eliminated via ligand-dependent proteolysis to downregulate receptor-mediated transcription.

scholarly journals Proteasome inhibitors: new class of antitumor agents

2003 ◽  
Vol 3 (4) ◽  
pp. 5-10
Author(s):  
Gordan Srkalović
Keyword(s):  
Antitumor Agents ◽  
Proteasome Inhibitors ◽  
26S Proteasome ◽  
Ubiquitin Proteasome Pathway ◽  
Cellular Processes ◽  
New Class ◽  
C Terminus ◽  
Ubiquitin Conjugating Enzyme ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway

The ubiquitin-proteasome pathway is the principal pathway for intracellular protein degradation1,2 (Fig 1). This pathway selectively degrades an extensive number of short-lived regulatory proteins involved in the control of normal cellular processes. In order to be degraded, proteins targeted by the ubiquitin-proteasome pathway are covalently tagged by polyubiquitination, via a three-step enzymatic process, which ultimately leads to their recognition and degradation, by the 26S proteasome in a highly specific and regulated manner. This process is accomplished by the sequential action of three enzymes: an ATP-dependent ubiquitin-activating enzyme (E1), an ubiquitin-conjugating enzyme (E2) and an ubiquitin-pro-tein ligase (E3).3 This cascade covalently links the C terminus of ubiquitin to a free amino group on the target protein, usually the ε-amino of a lysine residue.

The Ubiquitin-Proteasome Pathway an Emerging Anticancer Strategy for Therapeutics: A Patent Analysis

2015 ◽  
Vol 10 (2) ◽  
pp. 201-213 ◽  
Author(s):  
Chakresh Jain ◽  
Shivam Arora ◽  
Aparna Khanna ◽  
Money Gupta ◽  
Gulshan Wadhwa ◽  
...  
Keyword(s):  
Patent Analysis ◽  
Ubiquitin Proteasome Pathway ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway

scholarly journals Toll-like Receptor 4 Signaling in Ventilator-induced Diaphragm Atrophy

2012 ◽  
Vol 117 (2) ◽  
pp. 329-338 ◽  
Author(s):  
Willem-Jan M. Schellekens ◽  
Hieronymus W. H. van Hees ◽  
Michiel Vaneker ◽  
Marianne Linkels ◽  
P. N. Richard Dekhuijzen ◽  
...  
Keyword(s):  
Mechanical Ventilation ◽  
Caspase 3 ◽  
Toll Like Receptor ◽  
Wild Type ◽  
Toll Like Receptor 4 ◽  
Ubiquitin Proteasome Pathway ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway ◽  
Diaphragm Atrophy ◽  
Deficient Mice

Background Mechanical ventilation induces diaphragm muscle atrophy, which plays a key role in difficult weaning from mechanical ventilation. The signaling pathways involved in ventilator-induced diaphragm atrophy are poorly understood. The current study investigated the role of Toll-like receptor 4 signaling in the development of ventilator-induced diaphragm atrophy. Methods Unventilated animals were selected for control: wild-type (n = 6) and Toll-like receptor 4 deficient mice (n = 6). Mechanical ventilation (8 h): wild-type (n = 8) and Toll-like receptor 4 deficient (n = 7) mice.Myosin heavy chain content, proinflammatory cytokines, proteolytic activity of the ubiquitin-proteasome pathway, caspase-3 activity, and autophagy were measured in the diaphragm. Results Mechanical ventilation reduced myosin content by approximately 50% in diaphragms of wild-type mice (P less than 0.05). In contrast, ventilation of Toll-like receptor 4 deficient mice did not significantly affect diaphragm myosin content. Likewise, mechanical ventilation significantly increased interleukin-6 and keratinocyte-derived chemokine in the diaphragm of wild-type mice, but not in ventilated Toll-like receptor 4 deficient mice. Mechanical ventilation increased diaphragmatic muscle atrophy factor box transcription in both wild-type and Toll-like receptor 4 deficient mice. Other components of the ubiquitin-proteasome pathway and caspase-3 activity were not affected by ventilation of either wild-type mice or Toll-like receptor 4 deficient mice. Mechanical ventilation induced autophagy in diaphragms of ventilated wild-type mice, but not Toll-like receptor 4 deficient mice. Conclusion Toll-like receptor 4 signaling plays an important role in the development of ventilator-induced diaphragm atrophy, most likely through increased expression of cytokines and activation of lysosomal autophagy.

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