E3 Ubiquitin Ligase APC/CCdh1 Regulation of Phenylalanine Hydroxylase Stability and Function

Tyagi, Apoorvi; Sarodaya, Neha; Kaushal, Kamini; Chandrasekaran, Arun Pandian; Antao, Ainsley Mike; Suresh, Bharathi; Rhie, Byung Ho; Kim, Kye Seong; Ramakrishna, Suresh

doi:10.3390/ijms21239076

Cited by 12 publications

(4 citation statements)

References 59 publications

(68 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…PAH (phenylalanine hydroxylase, an enzyme which catalyzes the conversion of phenylalanine to tyrosine) has been associated with phenylketonuria, an autosomal recessive metabolic disorder. In HCC, a low expression of PAH has been reported as a prognostic marker for a poor prognosis [ 51 ].…”

Section: Discussionmentioning

confidence: 99%

A Minimal Subset of Seven Genes Associated with Tumor Hepatocyte Differentiation Predicts a Poor Prognosis in Human Hepatocellular Carcinoma

Desoteux

Louis

Bévant

et al. 2021

Cancers

View full text Add to dashboard Cite

Hepatocellular carcinoma (HCC) is a deadly cancer worldwide as a result of a frequent late diagnosis which limits the therapeutic options. Tumor progression in HCC is closely correlated with the dedifferentiation of hepatocytes, the main parenchymal cells in the liver. Here, we hypothesized that the expression level of genes reflecting the differentiation status of tumor hepatocytes could be clinically relevant in defining subsets of patients with different clinical outcomes. To test this hypothesis, an integrative transcriptomics approach was used to stratify a cohort of 139 HCC patients based on a gene expression signature established in vitro in the HepaRG cell line using well-controlled culture conditions recapitulating tumor hepatocyte differentiation. The HepaRG model was first validated by identifying a robust gene expression signature associated with hepatocyte differentiation and liver metabolism. In addition, the signature was able to distinguish specific developmental stages in mice. More importantly, the signature identified a subset of human HCC associated with a poor prognosis and cancer stem cell features. By using an independent HCC dataset (TCGA consortium), a minimal subset of seven differentiation-related genes was shown to predict a reduced overall survival, not only in patients with HCC but also in other types of cancers (e.g., kidney, pancreas, skin). In conclusion, the study identified a minimal subset of seven genes reflecting the differentiation status of tumor hepatocytes and clinically relevant for predicting the prognosis of HCC patients.

show abstract

Section: Discussionmentioning

confidence: 99%

A Minimal Subset of Seven Genes Associated with Tumor Hepatocyte Differentiation Predicts a Poor Prognosis in Human Hepatocellular Carcinoma

Desoteux

Louis

Bévant

et al. 2021

Cancers

View full text Add to dashboard Cite

show abstract

“…The following parameters were assayed serum tyrosinase was determined using (ab185435 kit) colorimetric assay method 15 , Serum Copper ions were determined using colorimetric assay kit at 580 nm according to 17 , Serum Fasting glucose levels were determined using (ab65333 kit) according to 16 , TAC in brain tissue was determined using (Cat. No-E-BC-K136-S) according to colorimetric assay adapted to 18 and MDA in brain tissue assayed using (ab118970) according to a method adapted to 19 .…”

Section: Biochemical Determinationsmentioning

confidence: 99%

Effect of Copper Sulphate Pollution and Its Antidote Penicillamine on Serum and Brain Tissues Markers of Albino Rats

Fawzy

Ahmed

Khamis

et al. 2022

Bulletin of Pharmaceutical Sciences. Assiut

View full text Add to dashboard Cite

Background:Copper is an essential trace element and is required for many metabolic functions. Aim of work: The present study was designed to study the negative impact of excess copper sulphate on the central neural function of albino rats and studying how its antidote d-penicillamine play role in improving its side effects. Material and methods: Seventy albino rats were divided into seven equal groups each containing 10 rats (G 1: control received distilled water) ; (G 2 : 0.1 LD 50 of CuSO 4 ) ; (G 3 : 0.2 LD 50 of CuSO 4 ) ; (G 4 : 0.4 LD 50 of CuSO 4 ) ; (G 5 : 0.1 LD 50 of CuSO 4 +100mg/kg/day of penicillamine) ; (G 6 : LD 50 of CuSO 4 .+100 mg/kg/day of penicillamine) and (G 7 : LD 50 of CuSO 4 + 100 mg /kg/day of penicillamine) for 30 days and at the end of the experiment all rats were sacrificed and blood samples and brain tissues were collected for biochemical assaying of fasting blood glucose (FBG), serum Cu level, serum tyrosinase activity, oxidative stress marker malondialdehyde (MDA) and total antioxidant activity (TAC). also, DNA determination of relative gene expression of cerebral adenosine monophosphate-activated protein kinase (AmpK), protein kinase (AKT), phosphatidylinositol-3-kinase (PI3K), cytochrome c oxidase (Cyto co ), and glucose -6-phosphate dehydrogenase (G6PD). Results: The results showed that administration of copper sulphate with different levels induced a significant increase in fasting blood glucose level, lipid peroxidation marker MDA, serum copper level, and serum tyrosinase activity, and a significant decrease in TAC. Moreover, copper sulphate administration elicited a significant downregulation ( AmpK, AKT, PI3K, Cytochrome c oxidase, G6PD).it could be approved that penicillamine could abolish the negative impact of copper sulphate on neural tissues and serum enzymes. Conclusion: D-penicillamine can reduce neurotoxicity and oxidative stress caused by copper pollution. Recommendations: Exposure to the pollution of copper must be controlled. Search for sensitive blood and neural markers for early detection of neurological disorders and further studies are needed to use its antidote d-penicillamine in the treatment of copper-induced pollution.

show abstract

“…Several reports have proposed mechanisms for the proteolytic degradation of PAH by the ubiquitin-dependent proteasomal degradation pathway 17 – 19 . We previously identified the specific E3 ligase APC/C Cdh1 and deubiquitinase USP19 responsible for modifying PAH wild-type (PAHwt) protein to balance the ubiquitination and deubiquitination of PAH in cells 19 , 20 . Our data demonstrated that PAHwt undergoes Cdh1-mediated ubiquitination and rapid degradation, which decreases the half-life of the PAHwt protein 19 .…”

Section: Introductionmentioning

confidence: 99%

“…We previously identified the specific E3 ligase APC/C Cdh1 and deubiquitinase USP19 responsible for modifying PAH wild-type (PAHwt) protein to balance the ubiquitination and deubiquitination of PAH in cells 19 , 20 . Our data demonstrated that PAHwt undergoes Cdh1-mediated ubiquitination and rapid degradation, which decreases the half-life of the PAHwt protein 19 . In contrast, USP19 reverses the ubiquitination of the PAHwt protein and extends its half-life.…”

Section: Introductionmentioning

confidence: 99%

Deubiquitinase USP19 extends the residual enzymatic activity of phenylalanine hydroxylase variants

Sarodaya

Tyagi

Kim

et al. 2022

Sci Rep

Self Cite

View full text Add to dashboard Cite

Phenylalanine hydroxylase (PAH) is a key enzyme in mammals that maintains the phenylalanine (Phe) concentration at an appropriate physiological level. Some genetic mutations in the PAH gene lead to destabilization of the PAH enzyme, leading to phenylketonuria (PKU). Destabilized PAH variants can have a certain amount of residual enzymatic activity that is sufficient for metabolism of Phe. However, accelerated degradation of those variants can lead to insufficient amounts of cellular PAH protein. The optimal protein level of PAH in cells is regulated by a balancing act between E3 ligases and deubiquitinating enzymes (DUBs). In this work, we analyzed the protein expression and stability of two PKU-linked PAH protein variants, R241C and R243Q, prevalent in the Asian population. We found that the tested PAH variants were highly ubiquitinated and thus targeted for rapid protein degradation. We demonstrated that USP19, a DUB that interacts with both PAH variants, plays a regulatory role by extending their half-lives. The deubiquitinating activity of USP19 prevents protein degradation and increases the abundance of both PAH protein variants. Thus, our study reveals a novel mechanism by which deubiquitinating activity of USP19 extends the residual enzymatic activity of PAH variants.

show abstract

E3 Ubiquitin Ligase APC/CCdh1 Regulation of Phenylalanine Hydroxylase Stability and Function

Cited by 12 publications

References 59 publications

A Minimal Subset of Seven Genes Associated with Tumor Hepatocyte Differentiation Predicts a Poor Prognosis in Human Hepatocellular Carcinoma

A Minimal Subset of Seven Genes Associated with Tumor Hepatocyte Differentiation Predicts a Poor Prognosis in Human Hepatocellular Carcinoma

Effect of Copper Sulphate Pollution and Its Antidote Penicillamine on Serum and Brain Tissues Markers of Albino Rats

Deubiquitinase USP19 extends the residual enzymatic activity of phenylalanine hydroxylase variants

Contact Info

Product

Resources

About