PP2A-B55β Antagonizes Cyclin E1 Proteolysis and Promotes Its Dysregulation in Cancer

Tan, YingMeei; Sun, Dahui; Jiang, Weijian; Klotz-Noack, Kathleen; Vashisht, Ajay A.; Wohlschlegel, James A.; Widschwendter, Martin; Spruck, Charles

doi:10.1158/0008-5472.can-13-1263

Cited by 18 publications

(13 citation statements)

References 31 publications

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“…8D). In mammalian cells, PP2A/B55β can dephosphorylate the N-and C-terminal phosphodegrons of CycE1 (Tan et al, 2014). Thus, the slower migrating form of CycE that we observe might be due to inhibition of PP2A/Twins (B55) by OA in Drosophila, which impacts the measured CycE/Cdk2 activity.…”

Section: Inhibition Of Pp2a Increases the T-loop Phosphorylation Of Cdk2mentioning

confidence: 71%

Protein phosphatase 2A promotes the transition to G0 during terminal differentiation in Drosophila

Sun

Buttitta

2015

Development

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Protein phosphatase type 2A complex (PP2A) has been known as a tumor suppressor for over two decades, but it remains unclear exactly how it suppresses tumor growth. Here, we provide data indicating a novel role for PP2A in promoting the transition to quiescence upon terminal differentiation in vivo. Using Drosophila eyes and wings as a model, we find that compromising PP2A activity during the final cell cycle prior to a developmentally controlled cell cycle exit leads to extra cell divisions and delays entry into quiescence. By systematically testing the regulatory subunits of Drosophila PP2A, we find that the B56 family member widerborst (wdb) is required for the role of PP2A in promoting the transition to quiescence. Cells in differentiating tissues with compromised PP2A retain high Cdk2 activity when they should be quiescent, and genetic epistasis tests demonstrate that ectopic Cyclin E/Cdk2 activity is responsible for the extra cell cycles caused by PP2A inhibition. The loss of wdb/PP2A function cooperates with aberrantly high Cyclin E protein levels, allowing cells to bypass a robust G0 late in development. This provides an example of how loss of PP2A can cooperate with oncogenic mutations in cancer. We propose that the PP2A complex plays a novel role in differentiating tissues to promote developmentally controlled quiescence through the regulation of Cyclin E/Cdk2 activity.

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Section: Inhibition Of Pp2a Increases the T-loop Phosphorylation Of Cdk2mentioning

confidence: 71%

Protein phosphatase 2A promotes the transition to G0 during terminal differentiation in Drosophila

Sun

Buttitta

2015

Development

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“…The finding that co-silencing CCNE1 rescues~50% of the aberrant phenotypes induced following SKP1 silencing identifies CCNE1 as the key misregulated target protein; however, as co-silencing did not completely prevent the CIN phenotypes, additional SCF targets are likely involved that remain to be identified. Under normal conditions, CCNE1 promotes cell cycle progression by activating CDK2 (Cyclin Dependent Kinase 2) at the G1/S-phase boundary, but it also functions in histone biosynthesis, centriole duplication, apoptotic inhibition and DNA replication [51,52]. Genomic amplification of CCNE1 occurs in many cancer types [41][42][43][44] and is an established driver of CIN, cellular transformation and cancer progression [39,45].…”

Section: Discussionmentioning

confidence: 99%

Reduced SKP1 Expression Induces Chromosome Instability through Aberrant Cyclin E1 Protein Turnover

Thompson

Baergen

Lichtensztejn

et al. 2020

Cancers

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Chromosome instability (CIN), or progressive changes in chromosome numbers, is an enabling feature of many cancers; however, the mechanisms giving rise to CIN remain poorly understood. To expand our mechanistic understanding of the molecular determinants of CIN in humans, we employed a cross-species approach to identify 164 human candidates to screen. Using quantitative imaging microscopy (QuantIM), we show that silencing 148 genes resulted in significant changes in CIN-associated phenotypes in two distinct cellular contexts. Ten genes were prioritized for validation based on cancer patient datasets revealing frequent gene copy number losses and associations with worse patient outcomes. QuantIM determined silencing of each gene-induced CIN, identifying novel roles for each as chromosome stability genes. SKP1 was selected for in-depth analyses as it forms part of SCF (SKP1, CUL1, FBox) complex, an E3 ubiquitin ligase that targets proteins for proteolytic degradation. Remarkably, SKP1 silencing induced increases in replication stress, DNA double strand breaks and chromothriptic events that were ascribed to aberrant increases in Cyclin E1 levels arising from reduced SKP1 expression. Collectively, these data reveal a high degree of evolutionary conservation between human and budding yeast CIN genes and further identify aberrant mechanisms associated with increases in chromothriptic events.

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“…Protein abundance of Cyclin E1 is controlled at several levels, including by ubiquitin-mediated proteolysis by E3 ligases FBXW7 and PARK2, both of which are frequently deleted in human tumors [107], and by PP2A-B55β, a phosphatase that also controls Cyclin E1 turnover [108]. Proteolytic cleavage of Cyclin E1 to low-molecular weight (LMW) isoforms by the elastase family of serine proteases enhances transformation [109,110] and increased expression of LMW isoforms is associated with poor outcome in breast cancer [111].…”

Section: Ccne1: a Unique Opportunity In High-grade Serous Ovarian Carmentioning

confidence: 99%

Pathogenesis and heterogeneity of ovarian cancer

Kroeger

Drapkin²

2017

Current Opinion in Obstetrics &Amp; Gynecology

243

218

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Purpose of reviewThe most common type of ovarian cancer, high-grade serous ovarian carcinoma (HGSOC), was originally thought to develop from the ovarian surface epithelium. However, recent data suggest that the cells that undergo neoplastic transformation and give rise to the majority of HGSOC are from the fallopian tube. This development has impacted both translational research and clinical practice, revealing new opportunities for early detection, prevention, and treatment of ovarian cancer.Recent findingsGenomic studies indicate that approximately 50% of HGSOC are characterized by mutations in genes involved in the homologous recombination pathway of DNA repair, especially BRCA1 and BRCA2. Clinical trials have demonstrated successful treatment of homologous recombination-defective cancers with poly-ribose polymerase inhibitors through synthetic lethality. Recently, amplification of CCNE1 was found to be another major factor in HGSOC tumorigenesis, accounting for approximately 20% of all cases. Interestingly, amplification of CCNE1 and mutation of homologous recombination repair genes are mutually exclusive in HGSOC.SummaryThe fallopian tube secretory cell is the cell of origin for the majority of ovarian cancers. Although it remains unclear what triggers neoplastic transformation of these cells, certain tumors exhibit loss of BRCA function or amplification of CCNE1. These alterations represent unique therapeutic opportunities in ovarian cancer.

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PP2A-B55β Antagonizes Cyclin E1 Proteolysis and Promotes Its Dysregulation in Cancer

Cited by 18 publications

References 31 publications

Protein phosphatase 2A promotes the transition to G0 during terminal differentiation in Drosophila

Protein phosphatase 2A promotes the transition to G0 during terminal differentiation in Drosophila

Reduced SKP1 Expression Induces Chromosome Instability through Aberrant Cyclin E1 Protein Turnover

Pathogenesis and heterogeneity of ovarian cancer

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