Senescence associated protein degradation

General Role ◽

Cellular Processes ◽

Ubiquitin Proteasome ◽

AbstractSenescent cells accumulate with age and contribute to pathologies associated to old age. The senescent program can be induced by pro-cancer stimuli or is developmentally controlled. In cells forced to senesce by expression of oncogenes or short telomeres, aberrant activation of the ERK/MAP kinase signaling pathway leads to selective protein degradation by the ubiquitin proteasome system. The proteins affected by this process control key cellular processes known to be defective in senescent cells. We discuss the evidence supporting a general role for senescence associated protein degradation for organismal aging.

A Nut for Every Bolt: Subunit-Selective Inhibitors of the Immunoproteasome and Their Therapeutic Potential

Cells ◽

10.3390/cells10081929 ◽

2021 ◽

Vol 10 (8) ◽

pp. 1929

Author(s):

Eva M. Huber ◽

Michael Groll

Keyword(s):

Cell Cycle Progression ◽

Therapeutic Potential ◽

Cell Signalling ◽

Selective Inhibition ◽

Cellular Processes ◽

Chemical Structures ◽

Phase Ii Clinical Trials ◽

Ubiquitin Proteasome ◽

Recent Trends

At the heart of the ubiquitin–proteasome system, the 20S proteasome core particle (CP) breaks down the majority of intracellular proteins tagged for destruction. Thereby, the CP controls many cellular processes including cell cycle progression and cell signalling. Inhibitors of the CP can suppress these essential biological pathways, resulting in cytotoxicity, an effect that is beneficial for the treatment of certain blood cancer patients. During the last decade, several preclinical studies demonstrated that selective inhibition of the immunoproteasome (iCP), one of several CP variants in mammals, suppresses autoimmune diseases without inducing toxic side effects. These promising findings led to the identification of natural and synthetic iCP inhibitors with distinct chemical structures, varying potency and subunit selectivity. This review presents the most prominent iCP inhibitors with respect to possible scientific and medicinal applications, and discloses recent trends towards pan-immunoproteasome reactive inhibitors that cumulated in phase II clinical trials of the lead compound KZR-616 for chronic inflammations.

Differential activation of ERK1,2 MAP kinase signaling pathway in mesenchymal stem cell from control and osteoporotic postmenopausal women

Journal of Cellular Biochemistry ◽

10.1002/jcb.20119 ◽

2004 ◽

Vol 92 (4) ◽

pp. 745-754 ◽

Cited By ~ 46

Author(s):

J. Pablo Rodríguez ◽

Susana Ríos ◽

Mireya Fernández ◽

J. Francisco Santibañez

Keyword(s):

Stem Cell ◽

Mesenchymal Stem Cell ◽

Map Kinase ◽

Postmenopausal Women ◽

Signaling Pathway ◽

Kinase Signaling ◽

Differential Activation ◽

Map Kinase Signaling ◽

Ccr4 is a novel shuttle factor required for ubiquitin-dependent proteolysis by the 26S proteasome

10.1101/2020.03.30.015370 ◽

2020 ◽

Author(s):

Ganapathi Kandasamy ◽

Ashis Kumar Pradhan ◽

R Palanimurugan

Keyword(s):

Saccharomyces Cerevisiae ◽

Protein Degradation ◽

Proteasomal Degradation ◽

Rna Degradation ◽

26S Proteasome ◽

Cellular Proteins ◽

Cellular Homeostasis ◽

Substrate Degradation ◽

Ubiquitin Proteasome

AbstractDegradation of short-lived and abnormal proteins are essential for normal cellular homeostasis. In eukaryotes, such unstable cellular proteins are selectively degraded by the ubiquitin proteasome system (UPS). Furthermore, abnormalities in protein degradation by the UPS have been linked to several human diseases. Ccr4 protein is a known component of the Ccr4-Not complex, which has established roles in transcription, mRNA de-adenylation and RNA degradation etc. Excitingly in this study, we show that Ccr4 protein has a novel function as a shuttle factor that promotes ubiquitin-dependent degradation of short-lived proteins by the 26S proteasome. Using a substrate of the well-studied ubiquitin fusion degradation (UFD) pathway, we found that its UPS-mediated degradation was severely impaired upon deletion of CCR4 in Saccharomyces cerevisiae. Additionally, we show that Ccr4 binds to cellular ubiquitin conjugates and the proteasome. In contrast to Ccr4, most other subunits of the Ccr4-Not complex proteins are dispensable for UFD substrate degradation. From our findings we conclude that Ccr4 functions in the UPS as a shuttle factor targeting ubiquitylated substrates for proteasomal degradation.

Selective COX-2 inhibitor regulates the MAP kinase signaling pathway in human osteoarthritic chondrocytes after induction of nitric oxide

International Journal of Molecular Medicine ◽

10.3892/ijmm.15.2.213 ◽

2005 ◽

Author(s):

Toshiaki Takahashi ◽

Yasuhiro Ogawa ◽

Kenichi Kitaoka ◽

Toshikazu Tani ◽

Yoshiki Uemura ◽

...

Keyword(s):

Nitric Oxide ◽

Map Kinase ◽

Signaling Pathway ◽

Kinase Signaling ◽

Osteoarthritic Chondrocytes ◽

Map Kinase Signaling ◽

Cox 2 ◽

E2A protein degradation by the ubiquitin-proteasome system is stage-dependent during muscle differentiation

Oncogene ◽

10.1038/sj.onc.1209793 ◽

2006 ◽

Vol 26 (3) ◽

pp. 441-448 ◽

Cited By ~ 11

Author(s):

L Sun ◽

J S Trausch-Azar ◽

A Ciechanover ◽

A L Schwartz

Keyword(s):

Protein Degradation ◽

Muscle Differentiation ◽

Ubiquitin Proteasome

Role of the p38 MAP-Kinase Signaling Pathway for Cx32 and Claudin-1 in the Rat Liver

Cell Communication & Adhesion ◽

10.1080/cac.10.4-6.437.443 ◽

2003 ◽

Vol 10 (4-6) ◽

pp. 437-443 ◽

Cited By ~ 18

Author(s):

Takashi Kojima ◽

Toshinobu Yamamoto ◽

Masaki Murata ◽

Mengdong Lan ◽

Ken-ichi Takano ◽

...

Keyword(s):

Map Kinase ◽

Signaling Pathway ◽

Rat Liver ◽

P38 Map Kinase ◽

Kinase Signaling ◽

Map Kinase Signaling ◽

Ubiquitin carboxyl-terminal hydrolases are required for period maintenance of the circadian clock at high temperature in Arabidopsis

Scientific Reports ◽

10.1038/s41598-019-53229-8 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 1

Author(s):

Ryosuke Hayama ◽

Peizhen Yang ◽

Federico Valverde ◽

Tsuyoshi Mizoguchi ◽

Ikuyo Furutani-Hayama ◽

...

Keyword(s):

Circadian Clock ◽

High Temperatures ◽

Elevated Temperatures ◽

Control Period ◽

26S Proteasome ◽

Cellular Processes ◽

Control Functions ◽

Ubiquitin Proteasome ◽

Carboxyl Terminal

AbstractProtein ubiquitylation participates in a number of essential cellular processes including signal transduction and transcription, often by initiating the degradation of specific substrates through the 26S proteasome. Within the ubiquitin-proteasome system, deubiquitylating enzymes (DUBs) not only help generate and maintain the supply of free ubiquitin monomers, they also directly control functions and activities of specific target proteins by modulating the pool of ubiquitylated species. Ubiquitin carboxyl-terminal hydrolases (UCHs) belong to an enzymatic subclass of DUBs, and are represented by three members in Arabidopsis, UCH1, UCH2 and UCH3. UCH1 and UCH2 influence auxin-dependent developmental pathways in Arabidopsis through their deubiquitylation activities, whereas biological and enzymatic functions of UCH3 remain unclear. Here, we demonstrate that Arabidopsis UCH3 acts to maintain the period of the circadian clock at high temperatures redundantly with UCH1 and UCH2. Whereas single uch1, uch2 and uch3 mutants have weak circadian phenotypes, the triple uch mutant displays a drastic lengthening of period at high temperatures that is more extreme than the uch1 uch2 double mutant. UCH3 also possesses a broad deubiquitylation activity against a range of substrates that link ubiquitin via peptide and isopeptide linkages. While the protein target(s) of UCH1-3 are not yet known, we propose that these DUBs act on one or more factors that control period length of the circadian clock through removal of their bound ubiquitin moieties, thus ensuring that the clock oscillates with a proper period even at elevated temperatures.