<scp>DNA</scp> and <scp>RNA</scp> binding by the Wilms' tumour gene 1 (<scp>WT</scp>1) protein +<scp>KTS</scp> and −<scp>KTS</scp> isoforms—From initial observations to recent global genomic analyses

Ullmark, Tove; Montano, Giorgia; Gullberg, Urban

doi:10.1111/ejh.13010

Cited by 19 publications

(18 citation statements)

References 116 publications

(285 reference statements)

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“…The presence or absence of KTS is an effect of an alternative splicing which is conserved in all vertebrates, suggesting that +KTS and −KTS are functionally distinct [ 15 ]. Indeed, both isoforms differ in affinity to DNA/RNA, with −KTS having a higher affinity to DNA, while +KTS binds preferentially to RNA [ 16 , 17 ]. The +KTS is expected to function in splicing and regulating stability of mRNA [ 17 , 18 , 19 ].…”

Section: Introductionmentioning

confidence: 99%

“…Indeed, both isoforms differ in affinity to DNA/RNA, with −KTS having a higher affinity to DNA, while +KTS binds preferentially to RNA [ 16 , 17 ]. The +KTS is expected to function in splicing and regulating stability of mRNA [ 17 , 18 , 19 ]. Isoforms +KTS and −KTS bind to different DNA sequence motifs as well as to different regions of target genes, resulting in a diverse influence on transcription.…”

Section: Introductionmentioning

confidence: 99%

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A Novel WT1 Mutation Identified in a 46,XX Testicular/Ovotesticular DSD Patient Results in the Retention of Intron 9

Sirokha

Gorodna

Vitrenko³

et al. 2021

Biology

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The 46,XX testicular DSD (disorder/difference of sexual development) and 46,XX ovotesticular DSD (46,XX TDSD and 46,XX OTDSD) phenotypes are caused by genetic rearrangements or point mutations resulting in imbalance between components of the two antagonistic, pro-testicular and pro-ovarian pathways; however, the genetic causes of 46,XX TDSD/OTDSD are not fully understood, and molecular diagnosis for many patients with the conditions is unavailable. Only recently few mutations in the WT1 (WT1 transcription factor; 11p13) gene were described in a group of 46,XX TDSD and 46,XX OTDSD individuals. The WT1 protein contains a DNA/RNA binding domain consisting of four zinc fingers (ZnF) and a three-amino acid (KTS) motif that is present or absent, as a result of alternative splicing, between ZnF3 and ZnF4 (±KTS isoforms). Here, we present a patient with 46,XX TDSD/OTDSD in whom whole exome sequencing revealed a heterozygous de novo WT1 c.1437A>G mutation within an alternative donor splice site which is used for −KTS WT1 isoform formation. So far, no mutation in this splice site has been identified in any patient group. We demonstrated that the mutation results in the retention of intron 9 in the mature mRNA of the 46,XX TDSD/OTDSD patient. In cases when the erroneous mRNA is translated, exclusively the expression of a truncated WT1 +KTS protein lacking ZnF4 and no −KTS protein occurs from the mutated allele of the patient. We discuss potential mechanisms and pathways which can be disturbed upon two conditions: Absence of Zn4F and altered +KTS/−KTS ratio.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A Novel WT1 Mutation Identified in a 46,XX Testicular/Ovotesticular DSD Patient Results in the Retention of Intron 9

Sirokha

Gorodna

Vitrenko³

et al. 2021

Biology

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“…6 The complexity of the effect of WT1 overexpression and loss in cancer cell physiology is probably in part due to the fact that WT1 has multiple isoforms with distinct biological functions. 48 Therefore, discriminating the oncogenic or tumour suppress effect of WT1 might facilitate the understanding in the biological role of WT1 in PDAC. 48 Therefore, discriminating the oncogenic or tumour suppress effect of WT1 might facilitate the understanding in the biological role of WT1 in PDAC.…”

Section: Discussionmentioning

confidence: 99%

Deubiquitinase inhibitor degrasyn suppresses metastasis by targeting USP5‐WT1‐E‐cadherin signalling pathway in pancreatic ductal adenocarcinoma

Zhu

et al. 2019

J Cellular Molecular Medi

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Wilm's tumour-1 (WT1) is overexpressed in pancreatic ductal adenocarcinoma (PDAC) and enhances metastasis. Deubiquitination stabilizes target proteins, and inhibiting deubiquitination facilitates the degradation of target proteins. However, whether inhibiting deubiquitination of WT1 facilitates its degradation and presents anti-cancer ability in PDAC is unknown. Here, we found that deubiquitinase inhibitor degrasyn rapidly induced the degradation of endogenous and exogenous WT1 through enhancing ubiquitination of WT1 followed by the up-regulation of E-cadherin. Knockdown of WT1 by short hairpin RNAs (shRNAs) inhibited metastasis and overexpression of WT1 partially prevented degrasyn-induced anti-metastasis activity, suggesting that degrasyn presents anti-metastasis activity partially through degrading WT1 protein. We further identified that USP5 deubiquitinated WT1 and stabilized its expression. The higher expressions of USP5 and WT1 are associated with tumour metastasis. More importantly, degrasyn inhibited the activity of USP5 and overexpression of USP5 partially prevented degrasyn-induced degradation of WT1 protein, suggesting that degrasyn degraded WT1 protein through inhibiting the activity of USP5. Finally, degrasyn reduced the tumorigenicity in a xenograft mouse model and reduced the metastasis in vivo. Our results indicate that degrasyn presents strong anti-cancer activity through USP5-WT1-E-cadherin signalling in PDAC.Therefore, degrasyn holds promise as cancer therapeutic agent in PDAC with high expressions of USP5 and WT1. K E Y W O R D S deubiquitinase inhibitor, pancreatic ductal adenocarcinoma, ubiquitin-specific protease, Wilm's tumour-1 | 1371 LI et aL.

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“…WT1 binds both DNA and RNA mainly through Zink-finger-domains (Figure 2) (reviewed in [156]) and has two isoform (KTS(+) and KTS(-)), which differ in the so-called KTS insert, which is present or absent following alternative splicing events [167]. Both isoforms have different binding specificities and regulate transcription depending on the isoform [168]. WT1 KTS (-) acts as an oncogene by inducing expression of the transcription factor BCL2 associated athanogene 3 (BAG3) [169], which interacts with 70 kD heat shock protein (HSP70) and sustains NFκB [170], thereby promoting an antiapoptotic effect [171].…”

Section: Wt1mentioning

confidence: 99%

RNA-Binding Proteins in Acute Leukemias

Schuschel

Helwig

Hüttelmaier

et al. 2020

IJMS

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Acute leukemias are genetic diseases caused by translocations or mutations, which dysregulate hematopoiesis towards malignant transformation. However, the molecular mode of action is highly versatile and ranges from direct transcriptional to post-transcriptional control, which includes RNA-binding proteins (RBPs) as crucial regulators of cell fate. RBPs coordinate RNA dynamics, including subcellular localization, translational efficiency and metabolism, by binding to their target messenger RNAs (mRNAs), thereby controlling the expression of the encoded proteins. In view of the growing interest in these regulators, this review summarizes recent research regarding the most influential RBPs relevant in acute leukemias in particular. The reported RBPs, either dysregulated or as components of fusion proteins, are described with respect to their functional domains, the pathways they affect, and clinical aspects associated with their dysregulation or altered functions.

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DNA and RNA binding by the Wilms' tumour gene 1 (WT1) protein +KTS and −KTS isoforms—From initial observations to recent global genomic analyses

Abstract: The Wilms' tumour gene 1 protein (WT1) is a zinc finger transcription factor found indispensable for foetal development. WT1 has also been implicated in the development of tumours in several organ systems, including acute myeloid leukaemia (AML).

Cited by 19 publications

References 116 publications

A Novel WT1 Mutation Identified in a 46,XX Testicular/Ovotesticular DSD Patient Results in the Retention of Intron 9

A Novel WT1 Mutation Identified in a 46,XX Testicular/Ovotesticular DSD Patient Results in the Retention of Intron 9

Deubiquitinase inhibitor degrasyn suppresses metastasis by targeting USP5‐WT1‐E‐cadherin signalling pathway in pancreatic ductal adenocarcinoma

RNA-Binding Proteins in Acute Leukemias

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