scholarly journals The RING Domain of cIAP1 Mediates the Degradation of RING-bearing Inhibitor of Apoptosis Proteins by Distinct Pathways

2008 ◽  
Vol 19 (7) ◽  
pp. 2729-2740 ◽  
Author(s):  
Herman H. Cheung ◽  
Stéphanie Plenchette ◽  
Chris J. Kern ◽  
Douglas J. Mahoney ◽  
Robert G. Korneluk
Keyword(s):  
Fas Ligand ◽  
Ring Domain ◽  
Inhibitor Of Apoptosis ◽  
Inhibitor Of Apoptosis Proteins ◽  
Down Regulation ◽  
Ubiquitin Proteasome Pathway ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway ◽  
Apoptosis Proteins

The Inhibitor of Apoptosis proteins (IAPs) are key repressors of apoptosis. Several IAP proteins contain a RING domain that functions as an E3 ubiquitin ligase involved in the ubiquitin-proteasome pathway. Here we investigated the interplay of ubiquitin-proteasome pathway and RING-mediated IAP turnover. We found that the CARD-RING domain of cIAP1 (cIAP1-CR) is capable of down-regulating protein levels of RING-bearing IAPs such as cIAP1, cIAP2, XIAP, and Livin, while sparing NAIP and Survivin, which do not possess a RING domain. To determine whether polyubiquitination was required, we tested the ability of cIAP1-CR to degrade IAPs under conditions that impair ubiquitination modifications. Remarkably, although the ablation of E1 ubiquitin-activating enzyme prevented cIAP1-CR–mediated down-regulation of cIAP1 and cIAP2, there was no impact on degradation of XIAP and Livin. XIAP mutants that were not ubiquitinated in vivo were readily down-regulated by cIAP1-CR. Moreover, XIAP degradation in response to cisplatin and doxorubicin was largely prevented in cIAP1-silenced cells, despite cIAP2 up-regulation. The knockdown of cIAP1 and cIAP2 partially blunted Fas ligand-mediated down-regulation of XIAP and protected cells from cell death. Together, these results show that the E3 ligase RING domain of cIAP1 targets RING-bearing IAPs for proteasomal degradation by ubiquitin-dependent and -independent pathways.

Down-Regulation of Inhibitor of Apoptosis Proteins by Deguelin Selectively Induces Apoptosis in Breast Cancer Cells

2006 ◽  
Vol 71 (1) ◽  
pp. 101-111 ◽  
Author(s):  
Xiang-Hong Peng ◽  
Prasanthi Karna ◽  
Ruth M. O'Regan ◽  
XiuJu Liu ◽  
Rajesh Naithani ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Inhibitor Of Apoptosis ◽  
Inhibitor Of Apoptosis Proteins ◽  
Down Regulation ◽  
Apoptosis Proteins

scholarly journals S-Nitrosylation of IRP2 Regulates Its Stability via the Ubiquitin-Proteasome Pathway

2004 ◽  
Vol 24 (1) ◽  
pp. 330-337 ◽  
Author(s):  
Sangwon Kim ◽  
Simon S. Wing ◽  
Prem Ponka
Keyword(s):  
Regulatory Protein ◽  
Untranslated Regions ◽  
Raw 264.7 Cells ◽  
Ubiquitin Proteasome Pathway ◽  
Functional Implications ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway ◽  
Iron Responsive Elements

ABSTRACT Nitric oxide (NO) is an important signaling molecule that interacts with different targets depending on its redox state. NO can interact with thiol groups resulting in S-nitrosylation of proteins, but the functional implications of this modification are not yet fully understood. We have reported that treatment of RAW 264.7 cells with NO caused a decrease in levels of iron regulatory protein 2 (IRP2), which binds to iron-responsive elements present in untranslated regions of mRNAs for several proteins involved in iron metabolism. In this study, we show that NO causes S-nitrosylation of IRP2, both in vitro and in vivo, and this modification leads to IRP2 ubiquitination followed by its degradation in the proteasome. Moreover, mutation of one cysteine (C178S) prevents NO-mediated degradation of IRP2. Hence, S-nitrosylation is a novel signal for IRP2 degradation via the ubiquitin-proteasome pathway.

scholarly journals c-Myc Proteolysis by the Ubiquitin-Proteasome Pathway: Stabilization of c-Myc in Burkitt's Lymphoma Cells

2000 ◽  
Vol 20 (7) ◽  
pp. 2423-2435 ◽  
Author(s):  
Mark A. Gregory ◽  
Stephen R. Hann
Keyword(s):  
Amino Acids ◽  
Phosphorylation Site ◽  
Burkitt’S Lymphoma ◽  
Burkitt's Lymphoma ◽  
Lymphoma Cells ◽  
Ubiquitin Proteasome Pathway ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway ◽  
Burkitt’S Lymphoma Cells

ABSTRACT The c-Myc oncoprotein is a transcription factor which is a critical regulator of cellular proliferation. Deregulated expression of c-Myc is associated with many human cancers, including Burkitt's lymphoma. The c-Myc protein is normally degraded very rapidly with a half-life of 20 to 30 min. Here we demonstrate that proteolysis of c-Myc in vivo is mediated by the ubiquitin-proteasome pathway. Inhibition of proteasome activity blocks c-Myc degradation, and c-Myc is a substrate for ubiquitination in vivo. Furthermore, an increase in c-Myc stability occurs in mitotic cells and is associated with inhibited c-Myc ubiquitination. Deletion analysis was used to identify regions of the c-Myc protein which are required for rapid proteolysis. We found that a centrally located PEST sequence, amino acids 226 to 270, is necessary for rapid c-Myc degradation, but not for ubiquitination. Also, N-terminal sequences, located within the first 158 amino acids of c-Myc, are necessary for both efficient c-Myc ubiquitination and subsequent degradation. We found that c-Myc is significantly stabilized (two- to sixfold) in many Burkitt's lymphoma-derived cell lines, suggesting that aberrant c-Myc proteolysis may play a role in the pathogenesis of Burkitt's lymphoma. Finally, mutation of Thr-58, a major phosphorylation site in c-Myc and a mutational hot spot in Burkitt's lymphoma, increases c-Myc stability; however, mutation of c-Myc is not essential for stabilization in Burkitt's lymphoma cells.

scholarly journals Sequential posttranslational modifications regulate PKC degradation

2016 ◽  
Vol 27 (2) ◽  
pp. 410-420 ◽  
Author(s):  
Yan Wang ◽  
Yangbo Wang ◽  
Huijun Zhang ◽  
Yingwei Gao ◽  
Chao Huang ◽  
...  
Keyword(s):  
Cross Talk ◽  
Posttranslational Modifications ◽  
Protein Function ◽  
Regulatory Mechanism ◽  
Down Regulation ◽  
Ubiquitin Proteasome Pathway ◽  
Different Types ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway

Cross-talk among different types of posttranslational modifications (PTMs) has emerged as an important regulatory mechanism for protein function. Here we elucidate a mechanism that controls PKCα stability via a sequential cascade of PTMs. We demonstrate that PKCα dephosphorylation decreases its sumoylation, which in turn promotes its ubiquitination and ultimately enhances its degradation via the ubiquitin-proteasome pathway. These findings provide a molecular explanation for the activation-induced down-regulation of PKC proteins.

Reproductive Cytotoxicity Is Predicted by Magnetic Resonance Microscopy and Confirmed by Ubiquitin–Proteasome Immunohistochemistry in a Theophylline-Induced Model of Rat Testicular and Epididymal Toxicity

2005 ◽  
Vol 11 (4) ◽  
pp. 300-312 ◽  
Author(s):  
M.W. Tengowski ◽  
P. Sutovsky ◽  
L.W. Hedlund ◽  
D.J. Guyot ◽  
J.E. Burkhardt ◽  
...  
Keyword(s):  
Magnetic Resonance ◽  
Phosphodiesterase Inhibitor ◽  
Magnetic Resonance Microscopy ◽  
Vascular Perfusion ◽  
Ubiquitin Proteasome Pathway ◽  
Organ Systems ◽  
Water Signal ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway

This study investigated the testicular changes in the rat induced by the nonspecific phosphodiesterase inhibitor, theophylline using magnetic resonance microscopy (MRM) and ubiquitin immunostaining techniques.In vivoT1- and T2-weighted images were acquired at 2 T under anesthesia. Increased signal observed in the theophylline-treated rats suggests that leakage of MRM contrast was occurring.In vivoMRM results indicate that day 16 testis displayed an increased T1-weighted water signal in the area of the seminiferous tubule that decreased by day 32. These findings were validated by histopathology, suggesting thatin vivoMRM has the sensitivity to predict changes in testis and epididymal tissues. The participation of the ubiquitin system was investigated, using probes for various markers of the ubiquitin-proteasome pathway. MRM can be used to detect subtle changes in the vascular perfusion of organ systems, and the up-regulation/mobilization of ubiquitin-proteasome pathway may be one of the mechanisms used in theophylline-treated epididymis to remove damaged cells before storage in the cauda epididymis. The combined use ofin vivoMRM and subsequent tissue or seminal analysis for the presence of ubiquitin in longitudinal studies may become an important biomarker for assessing testis toxicities drug studies.

scholarly journals Paeoniflorin inhibits glioblastoma growth in vivo and in vitro: a role for the Triad3A-dependent ubiquitin proteasome pathway in TLR4 degradation

2018 ◽  
Vol Volume 10 ◽  
pp. 887-897 ◽  
Author(s):  
Zhaotao Wang ◽  
Guoyong Yu ◽  
Zhi Liu ◽  
Jianwei Zhu ◽  
Chen Chen ◽  
...  
Keyword(s):  
Ubiquitin Proteasome Pathway ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway

scholarly journals The Yeast C-Type Cyclin Ctk2p Is Phosphorylated and Rapidly Degraded by the Ubiquitin-Proteasome Pathway

1999 ◽  
Vol 19 (4) ◽  
pp. 2527-2534 ◽  
Author(s):  
Guillaume Hautbergue ◽  
Valérie Goguel
Keyword(s):  
Cell Cycle ◽  
Rna Polymerase Ii ◽  
Cyclin Dependent Kinase ◽  
Transcription Control ◽  
Ubiquitin Proteasome Pathway ◽  
Ubiquitin Proteasome ◽  
Steady State Levels ◽  
Proteasome Pathway ◽  
Carboxy Terminal

ABSTRACT The yeast CTDK-I complex has been implicated in phosphorylation of the carboxy-terminal domain of the RNA polymerase II and in transcription control. It is composed of three polypeptides: Ctk1p and Ctk2p, a cyclin-dependent kinase and a C-type cyclin subunit, respectively; and Ctk3p, a third subunit of unknown function. Cyclins are regulatory proteins whose expression is tightly controlled at the protein level. In this study, we examined the regulation of Ctk2p expression in vivo. Surprisingly, unlike what has been described for cell cycle cyclins, steady-state levels of Ctk2p are composed of two relatively abundant forms, one of them phosphorylated. We show that this phosphorylated form is extremely unstable (half-life, 5 min) and that rapid proteolysis of Ctk2p exhibits growth-related regulation. Furthermore, our data establish that similar to the case for other naturally short-lived proteins, Ctk2p degradation is mediated by the ubiquitin-proteasome pathway. This is the first demonstration that a C-type cyclin is phosphorylated and targeted to the proteasome. Strikingly, neither phosphorylation nor destruction of Ctk2p requires its associated kinase Ctk1p, a feature fundamentally different from that which has been observed for cell cycle cyclins.

Sign in / Sign up

Export Citation Format

Share Document