PTENβ is an alternatively translated isoform of PTEN that regulates rDNA transcription

Liang, Hui; Chen, Xi; Yin, Qi; Ruan, Danhui; Zhao, Xuyang; Zhang, Cong; McNutt, Michael A.; Yin, Yuxin

doi:10.1038/ncomms14771

Cited by 102 publications

(126 citation statements)

References 58 publications

Supporting

Mentioning

120

Contrasting

Order By: Relevance

“…patients, and this absence of nuclear PTEN was correlated with the overexpression of FBXO22 in cancer tissues. Besides canonical PTEN protein, recent studies also identified two evolutionarily conserved translational variants of PTEN, designated PTENα (PTEN-long or PTEN-L) and PTENβ [47][48][49] . They are respectively translated from a CUG site and an AUU site in the 5′-untranslated region of PTEN mRNA, thus containing an N-terminal extension of 173 and 146 amino acids followed by the 403 amino acids of PTEN.…”

Section: Discussionmentioning

confidence: 99%

FBXO22 degrades nuclear PTEN to promote tumorigenesis

Zhang

et al. 2020

Nat Commun

View full text Add to dashboard Cite

Nuclear localization of PTEN is essential for its tumor suppressive role, and loss of nuclear PTEN is more prominent than cytoplasmic PTEN in many kinds of cancers. However, nuclear PTEN-specific regulatory mechanisms were rarely reported. Based on the finding that nuclear PTEN is more unstable than cytoplasmic PTEN, here we identify that F-box only protein 22 (FBXO22) induces ubiquitylation of nuclear but not cytoplasmic PTEN at lysine 221, which is responsible for the degradation of nuclear PTEN. FBXO22 plays a tumor-promoting role by ubiquitylating and degrading nuclear PTEN. In accordance, FBXO22 is overexpressed in various cancer types, and contributes to nuclear PTEN downregulation in colorectal cancer tissues. Cumulatively, our study reports the mechanism to specifically regulate the stability of nuclear PTEN, which would provide the opportunity for developing therapeutic strategies aiming to achieve complete reactivation of PTEN as a tumor suppressor.

show abstract

Section: Discussionmentioning

confidence: 99%

FBXO22 degrades nuclear PTEN to promote tumorigenesis

Zhang

et al. 2020

Nat Commun

View full text Add to dashboard Cite

show abstract

“…This suggests that distinct biological mechanisms underlie the differential presentations, and understanding these differences will be critical to the eventual treatment of these disorders. While it is possible that these different mechanisms are the direct result of lipid phosphatase activity at the plasma membrane, ASD-associated mutations may specifically disrupt another of PTEN's cellular functions 67,68 . Supporting this idea, some ASD-associated mutations are excluded from the nucleus and lead to neuronal hypertrophy, but this phenotype can be rescued by artificial direction to the nucleus 69 .…”

Section: Discussionmentioning

confidence: 99%

A saturation mutagenesis approach to understanding PTEN lipid phosphatase activity and genotype-phenotypes relationships

Mighell

Evans-Dutson

O’Roak

2018

Preprint

View full text Add to dashboard Cite

Phosphatase and tensin homolog (PTEN) is a tumor suppressor frequently mutated in diverse cancers. Germline PTEN mutations are also associated with a range of clinical outcomes, including PTEN hamartoma tumor syndrome (PHTS) and autism spectrum disorder (ASD). To empower new insights into PTEN function and clinically relevant genotype-phenotype relationships, we systematically evaluated the effect of PTEN mutations on lipid phosphatase activity in vivo. Using a massively parallel approach that leverages an artificial humanized yeast model, we derived high-confidence estimates of functional impact for 7,244 single amino acid PTEN variants (86% of possible). These data uncovered novel insights into PTEN protein structure, biochemistry, and mutation tolerance. Variant functional scores can reliably discriminate likely pathogenic from benign alleles. Further, 32% of ClinVar unclassified missense variants are phosphatase deficient in our assay, supporting their reclassification. ASD associated mutations generally had less severe fitness scores relative to PHTS associated mutations (p = 7.16x10 -5 ) and a higher fraction of hypomorphic mutations, arguing for continued genotype-phenotype studies in larger clinical datasets that can further leverage these rich functional data. MAIN TEXTRecent large-scale exome sequencing studies have highlighted the abundance of protein-coding variation in the human population 1 . It remains challenging to predict variant pathogenicity and clinical outcomes, especially for genes with pleiotropic effects. With most rare variants private to a single family or individual, using traditional approaches to establish pathogenicity such as variant segregation within a pedigree or identification in independent patients is infeasible. Even for well-studied genes, hundreds of variants are currently defined as variants of uncertain significance (VUS). Moreover, purely computational approaches still suffer from high false positive rates 2 and subjective interpretations that limit the clinical utility of these predictions. To address these challenges for genes of clinical importance, one proposed approach is to prospectively measure the functional effects of all possible mutations, allowing these empirical data to be integrated into the clinical assessment of novel rare variants 3,4 . Historically, these types of functional assays have been conducted in a serial nature, which limits scalability, and often only within a portion of the protein of interest. While there are some notable examples of whole-gene brute force saturation mutagenesis, e.g., TP535 , new more scalable experimental paradigms are being developed that allow the functional dissection of the effects of thousands of genetic mutations in parallel 6 . These approaches leverage recent advances in DNA synthesis and sequencing technologies and have proven particularly valuable in understanding the effects of mutations in cancer-associated genes 7,8 . With these issues in mind, we have developed a saturation mutagenesis approach to...

show abstract

“…Generally, these codons appear to be the most efficient near-cognate start codons, and they are embedded in a good Kozak consensus sequence in causative genes for FXTAS and c9ALS/FTD [25,30,53,54]. Based on previous studies concerning structural requirements for translation initiation, we initially assumed, that a stable hairpin formed by expanded CAG repeats downstream from the AAG codons would increase the likelihood of initiation at these sites [82][83][84][85]. Why does RAN translation in the glutamine frame initiate from CUU and ACU codons in a weak Kozak motif?…”

Section: Discussionmentioning

confidence: 99%

RAN translation of the expanded CAG repeats in the SCA3 disease context

Jazurek-Ciesiolka

Ciesiolka

Komur

et al. 2020

Preprint

View full text Add to dashboard Cite

ACKNOWLEDGEMENTSThis work is dedicated to the memory of Professor Wlodzimierz J. Krzyzosiak. We thank Professor Marta Olejniczak from Department of Genome Engineering for reviewing the manuscript and every day stimulating discussions. We thank Professor Jerzy Ciesiolka from Department of RNA Biochemistry for helpful suggestions. The confocal microscopy analyses were performed in the ABSTRACT Spinocerebellar ataxia type 3 (SCA3) is a progressive neurodegenerative disorder caused by a CAG repeat expansion in the ATXN3 gene encoding the ataxin-3 protein. Despite extensive research the exact pathogenic mechanisms of SCA3 are still not understood in depth. In the present study, to gain insight into the toxicity induced by the expanded CAG repeats in SCA3, we comprehensively investigated repeat-associated non-ATG (RAN) translation in various cellular models expressing translated or non-canonically translated ATXN3 sequences with an increasing number of CAG repeats.We demonstrate that two SCA3 RAN proteins, polyglutamine (polyQ) and polyalanine (polyA), are found only in the case of CAG repeats of pathogenic length. Despite having distinct cellular localization, RAN polyQ and RAN polyA proteins are very often coexpressed in the same cell, impairing nuclear integrity and inducing apoptosis. We provide for the first time mechanistic insights into SCA3 RAN translation indicating that ATXN3 sequences surrounding the repeat region have an impact on SCA3 RAN translation initiation and efficiency. We revealed that RAN translation of polyQ proteins starts at noncognate codons upstream of the CAG repeats, whereas RAN polyA proteins are likely translated within repeats. Furthermore, integrated stress response activation enhances SCA3 RAN translation. We suggest that RAN translation in SCA3 is a common event substantially contributing to SCA3 pathogenesis and that the ATXN3 sequence context plays an important role in triggering this unconventional translation. KEYWORDSSCA3, CAG repeat expansion, RAN translation, translation initiation, non-cognate initiation codon, integrated stress response ABBREVIATIONS ATXN3 -ataxin-3, c9ALS/FTD -c9orf72 amyotrophic lateral sclerosis/frontotemporal dementia, CHOP -C/EBP homologous protein, DM1 -myotonic dystrophy type 1 and type 2, ER -endoplasmic reticulum, FECD -Fuchs' endothelial corneal dystrophy, FXTAS -fragile X tremor ataxia syndrome, iMet-tRNAinitiator Met-tRNA, ISR -integrated stress response, MetAPs -methionine aminopeptidases, NAT -Nterminal acetyltransferase, NPC -nuclear pore complex, polyApolyalanine, polyQpolyglutamine, polySpolyserine, RAN translation -repeat associated non-ATG translation, SA -sodium arsenite, SCA3 -spinocerebellar ataxia type 3, TG -thapsigargin INTRODUCTIONSpinocerebellar ataxia type 3 (SCA3) is the most common form of dominantly inherited ataxia in the world and one of nine polyglutamine (polyQ) neurodegenerative diseases. This progressive and fatal disorder is primarily characterized by neuronal dysfunction and degeneration of the cerebellum and functionall...

show abstract

PTENβ is an alternatively translated isoform of PTEN that regulates rDNA transcription

Cited by 102 publications

References 58 publications

FBXO22 degrades nuclear PTEN to promote tumorigenesis

FBXO22 degrades nuclear PTEN to promote tumorigenesis

A saturation mutagenesis approach to understanding PTEN lipid phosphatase activity and genotype-phenotypes relationships

RAN translation of the expanded CAG repeats in the SCA3 disease context

Contact Info

Product

Resources

About