Photoreceptor Cell Development Requires CDHR1a Protein Stability Controlled by Siah E3 Ubiquitin Ligase During Zebrafish Eye Development

AbstractTimed degradation of the cyclin-dependent kinase inhibitor p27Kip1 by the E3 ubiquitin ligase F-box protein SKP2 is critical for T-cell progression into cell cycle, coordinating proliferation and differentiation processes. SKP2 expression is regulated by mitogenic stimuli and by Notch signaling, a key pathway in T-cell development and in T-cell acute lymphoblastic leukemia (T-ALL); however, it is not known whether SKP2 plays a role in the development of T-ALL. Here, we determined that SKP2 function is relevant for T-ALL leukemogenesis, whereas is dispensable for T-cell development. Targeted inhibition of SKP2 by genetic deletion or pharmacological blockade markedly inhibited proliferation of human T-ALL cells in vitro and antagonized disease in vivo in murine and xenograft leukemia models, with little effect on normal tissues. We also demonstrate a novel feed forward feedback loop by which Notch and IL-7 signaling cooperatively converge on SKP2 induction and cell cycle activation. These studies show that the Notch/SKP2/p27Kip1 pathway plays a unique role in T-ALL development and provide a proof-of-concept for the use of SKP2 as a new therapeutic target in T-cell acute lymphoblastic leukemia (T-ALL).

Download Full-text

E3 Ubiquitin Ligase APC/CCdh1 Negatively Regulates FAH Protein Stability by Promoting Its Polyubiquitination

International Journal of Molecular Sciences ◽

10.3390/ijms21228719 ◽

2020 ◽

Vol 21 (22) ◽

pp. 8719

Author(s):

Kamini Kaushal ◽

Sang Hyeon Woo ◽

Apoorvi Tyagi ◽

Dong Ha Kim ◽

Bharathi Suresh ◽

...

Keyword(s):

Protein Stability ◽

Ubiquitin Ligase ◽

Protein Level ◽

E3 Ubiquitin Ligase ◽

Degradation Pathway ◽

Type I ◽

E3 Ligases ◽

Normal Tissues ◽

Key Factor ◽

Hereditary Tyrosinemia

Fumarylacetoacetate hydrolase (FAH) is the last enzyme in the degradation pathway of the amino acids tyrosine and phenylalanine in mammals that catalyzes the hydrolysis of 4-fumarylacetoacetate into acetoacetate and fumarate. Mutations of the FAH gene are associated with hereditary tyrosinemia type I (HT1), resulting in reduced protein stability, misfolding, accelerated degradation and deficiency in functional proteins. Identifying E3 ligases, which are necessary for FAH protein stability and degradation, is essential. In this study, we demonstrated that the FAH protein level is elevated in liver cancer tissues compared to that in normal tissues. Further, we showed that the FAH protein undergoes 26S proteasomal degradation and its protein turnover is regulated by the anaphase-promoting complex/cyclosome-Cdh1 (APC/C)Cdh1 E3 ubiquitin ligase complex. APC/CCdh1 acts as a negative stabilizer of FAH protein by promoting FAH polyubiquitination and decreases the half-life of FAH protein. Thus, we envision that Cdh1 might be a key factor in the maintenance of FAH protein level to regulate FAH-mediated physiological functions.

Download Full-text

Weak binding to E3 ubiquitin ligase c-Cbl increases EGFRvA protein stability

FEBS Letters ◽

10.1002/1873-3468.12166 ◽

2016 ◽

Vol 590 (9) ◽

pp. 1345-1353 ◽

Cited By ~ 1

Author(s):

Fei Song ◽

Min Zhou ◽

Biao Wang ◽

Bizhi Shi ◽

Hua Jiang ◽

...

Keyword(s):

Protein Stability ◽

Ubiquitin Ligase ◽

E3 Ubiquitin Ligase ◽

Weak Binding

Download Full-text

pVHL regulates protein stability of TCF/LEF transcription factor family via ubiquitin-independent proteasomal degradation

10.1101/2021.10.14.464355 ◽

2021 ◽

Author(s):

Caixia Wang ◽

Xiaozhi Rong ◽

Haifeng Zhang ◽

Bo Wang ◽

Yan Bai ◽

...

Keyword(s):

Gene Expression ◽

Transcription Factors ◽

Protein Stability ◽

Ubiquitin Ligase ◽

Target Gene ◽

E3 Ubiquitin Ligase ◽

Proteasomal Degradation ◽

26S Proteasome ◽

Cell Fate Decisions ◽

Target Gene Expression

The Wnt/β-catenin signaling pathway plays key roles in development and adult tissue homeostasis by controlling cell proliferation and cell fate decisions. In this pathway, transcription factors TCF/LEFs are the key components to repress target gene expression by recruiting co-repressors or to activate target gene expression by recruiting β-catenin when the Wnt signals are absent or present, respectively. While progress has been made in our understanding of Wnt signaling regulation, the underlying mechanism that regulates the protein stability of the TCF/LEF family is far less clear. Here, we show that von Hippel-Lindau protein (pVHL), which is the substrate recognition component in an E3 ubiquitin ligase complex, controls TCF/LEF protein stability. Unexpectedly, pVHL directly binds to TCF/LEFs and promotes their proteasomal degradation independent of E3 ubiquitin ligase activity. Knockout of vhl in zebrafish embryos leads to a reduction of dorsal habenular neurons and this effect is upstream of dorsal habenular neurons phenotype in tcf7l2-null mutants. Our study uncovers a previously unknown mechanism for the protein stability regulation of the TCF/LEF transcription factors and demonstrates that pVHL contains a 26S proteasome binding domain that drives ubiquitin-independent proteasomal degradation. These findings provide new insights into the ubiquitin-independent actions of pVHL and uncover novel mechanistical regulation of Wnt/β-catenin signaling.

Download Full-text