PEA15 Regulates the DNA Damage-Induced Cell Cycle Checkpoint and Oncogene-Directed Transformation

Nagarajan, Arvindhan; Dogra, Shaillay Kumar; Liu, Alex Y.; Green, Michael R.; Wajapeyee, Narendra

doi:10.1128/mcb.01542-13

Cited by 21 publications

(11 citation statements)

References 52 publications

(63 reference statements)

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“…The DDR‐induced S‐phase arrest was accompanied by a concomitant decrease in levels of CDK1, an essential kinase for progression through the G2/M phase of the cell cycle . This decrease in CDK1 is in agreement with previously reported transcriptional control of CDK1 by components of the DDR pathway …”

Section: Discussionsupporting

confidence: 91%

The synthetic retinoid ST1926 as a novel therapeutic agent in rhabdomyosarcoma

Basma

Ghayad

Rammal

et al. 2015

Intl Journal of Cancer

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Rhabdomyosarcoma (RMS) is the most frequent soft tissue sarcoma in children. Despite multiple attempts at intensifying chemotherapeutic approaches to treatment, only moderate improvements in survival have been made for patients with advanced disease. Retinoic acid is a differentiation agent that has shown some antitumor efficacy in RMS cells in vitro; however, the effects are of low magnitude. E23-(4 0 -hydroxyl-3 0 -adamantylbiphenyl-4-yl) acrylic acid (ST1926) is a novel orally available synthetic atypical retinoid, shown to have more potent activity than retinoic acid in several types of cancer cells. We used in vitro and in vivo models of RMS to explore the efficacy of ST1926 as a possible therapeutic agent in this sarcoma. We found that ST1926 reduced RMS cell viability in all tested alveolar (ARMS) and embryonal (ERMS) RMS cell lines, at readily achievable micromolar concentrations in mice. ST1926 induced an early DNA damage response (DDR), which led to increase in apoptosis, in addition to S-phase cell cycle arrest and a reduction in protein levels of the cell cycle kinase CDK1. Effects were irrespective of TP53 mutational status. Interestingly, in ARMS cells, ST1926 treatment decreased PAX3-FOXO1 fusion oncoprotein levels, and this suppression occurred at a post-transcriptional level. In vivo, ST1926 was effective in inhibiting growth of ARMS and ERMS xenografts, and induced a prominent DDR. We conclude that ST1926 has preclinical efficacy against RMS, and should be further developed in this disease in clinical trials.Rhabdomyosarcoma (RMS) is the most frequent soft tissue sarcoma, and the third most common solid tumor in children. 1 It accounts for 6% of all childhood cancers and approximately 40% of soft tissue sarcomas. 2,3 RMS likely arises from primitive mesenchymal progenitors that have undergone a limited program of myogenic differentiation, because of the expression of skeletal myogenic proteins in RMS tumors. 1,4 Rhabdomyosarcoma occurs in two major histological subtypes: embryonal (ERMS) and alveolar (ARMS) histologies. 1,4 ARMS is associated with a chromosomal translocation between the PAX3 or PAX7 and FOXO1 genes in approximately 55 and 22% of cases, respectively. 5 Patients presenting with ARMS tumors usually have a worse prognosis as compared to ERMS. The PAX-FOXO1 fusion transcript has been shown to exhibit a more potent transcriptional activation function than the PAX proteins alone, 6 and contributes to the invasive phenotype of ARMS, 7,8 making it an interesting target for therapeutic intervention. 9 Despite multiple attempts at intensifying chemotherapeutic approaches to treatment, limited improvements in survival have been made for patients with advanced-stage disease or recurrent RMS over the past 10 years. [10][11][12] This underlies the need for novel therapeutic approaches. 10,13 Retinoic acid is a morphogen and a major regulator of cellular proliferation, apoptosis and differentiation, 14 and has been investigated as differentiation therapy in multiple types of cancer, contributi...

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Section: Discussionsupporting

confidence: 91%

The synthetic retinoid ST1926 as a novel therapeutic agent in rhabdomyosarcoma

Basma

Ghayad

Rammal

et al. 2015

Intl Journal of Cancer

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“…PEA-15 was reported to play a role in promoting DNA damage-induced G 2 /M checkpoint. DNA damage stabilizes PEA-15 by preventing polyubiquitination and proteasome-mediated degradation [ 47 ], similar to the mechanism of DNA damage-induced upregulation of other tumor suppressor proteins, such as p53 [ 48 ]. PEA-15 protein levels oscillate throughout the cell cycle with peak expression during G 2 /M, and PEA-15 knockdown results in G 2 /M checkpoint defect due to increased activation of CDC25C by ERK1/2, which subsequently elevates cyclin-dependent kinase CDK1/cyclin B activity [ 47 ].…”

Section: Protective Roles Of Pea-15 and Modulations Of Pea-15 Funcmentioning

confidence: 99%

“…DNA damage stabilizes PEA-15 by preventing polyubiquitination and proteasome-mediated degradation [ 47 ], similar to the mechanism of DNA damage-induced upregulation of other tumor suppressor proteins, such as p53 [ 48 ]. PEA-15 protein levels oscillate throughout the cell cycle with peak expression during G 2 /M, and PEA-15 knockdown results in G 2 /M checkpoint defect due to increased activation of CDC25C by ERK1/2, which subsequently elevates cyclin-dependent kinase CDK1/cyclin B activity [ 47 ]. PEA-15 controls cell cycle progression by inhibiting ERK-dependent, c-JUN-mediated transcriptional activation of CDK6, and regulates RAS-mediated neoplastic transformation by suppressing CDK6 activity [ 47 ].…”

Section: Protective Roles Of Pea-15 and Modulations Of Pea-15 Funcmentioning

confidence: 99%

“…PEA-15 protein levels oscillate throughout the cell cycle with peak expression during G 2 /M, and PEA-15 knockdown results in G 2 /M checkpoint defect due to increased activation of CDC25C by ERK1/2, which subsequently elevates cyclin-dependent kinase CDK1/cyclin B activity [ 47 ]. PEA-15 controls cell cycle progression by inhibiting ERK-dependent, c-JUN-mediated transcriptional activation of CDK6, and regulates RAS-mediated neoplastic transformation by suppressing CDK6 activity [ 47 ]. PEA-15 was also found to be epigenetically silenced through promotor DNA hypermethylation in colorectal, lung, and breast cancer tissues [ 47 ].…”

Section: Protective Roles Of Pea-15 and Modulations Of Pea-15 Funcmentioning

confidence: 99%

“…PEA-15 controls cell cycle progression by inhibiting ERK-dependent, c-JUN-mediated transcriptional activation of CDK6, and regulates RAS-mediated neoplastic transformation by suppressing CDK6 activity [ 47 ]. PEA-15 was also found to be epigenetically silenced through promotor DNA hypermethylation in colorectal, lung, and breast cancer tissues [ 47 ]. Another study showed that in human diploid fibroblast (HDF) senescent cells, PEA-15 knockdown significantly progressed G 1 arrested cells to S-phase through nuclear translocation of ERK1/2, and activated cell proliferation [ 49 ].…”

Section: Protective Roles Of Pea-15 and Modulations Of Pea-15 Funcmentioning

confidence: 99%

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On the Quest of Cellular Functions of PEA-15 and the Therapeutic Opportunities

Wei

2015

Pharmaceuticals

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Phosphoprotein enriched in astrocytes, 15 KDa (PEA-15), a ubiquitously expressed small protein in all mammals, is known for decades for its potent interactions with various protein partners along distinct biological pathways. Most notable interacting partners of PEA-15 include extracellular signal-regulated kinase 1 and 2 (ERK1/2) in the mitogen activated protein kinase (MAPK) pathway, the Fas-associated death domain (FADD) protein involving in the formation of the death-inducing signaling complex (DISC), and the phospholipase D1 (PLD1) affecting the insulin sensitivity. However, the actual cellular functions of PEA-15 are still mysterious, and the question why this protein is expressed in almost all cell and tissue types remains unanswered. Here we synthesize the most recent structural, biological, and clinical studies on PEA-15 with emphases on its anti-apoptotic, anti-proliferative, and anti-inflammative properties, and propose a converged protective role of PEA-15 that maintains the balance of death and survival in different cell types. Under conditions that this delicate balance is unsustainable, PEA-15 may become pathological and lead to various diseases, including cancers and diabetes. Targeting PEA-15 interactions, or the use of PEA-15 protein as therapeutics, may provide a wider window of opportunities to treat these diseases.

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Regulatory networks and 5′ partner usage of miRNA host gene fusions in breast cancer

Hafstað

Søkilde

Häkkinen

et al. 2022

Intl Journal of Cancer

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Genomic rearrangements in cancer cells can create gene fusions where the juxtaposition of two different genes leads to the production of chimeric proteins or altered gene expression through promoter-swapping. We have previously shown that fusion transcripts involving microRNA (miRNA) host genes contribute to deregulation of miRNA expression regardless of the protein-coding potential of these transcripts. Many different genes can also be used as 5 0 partners by a miRNA host gene in what we named recurrent miRNA-convergent fusions. Here, we have explored the properties of 5 0 partners in fusion transcripts that involve miRNA hosts in breast tumours from The Cancer Genome Atlas (TCGA). We hypothesised that firstly, 5 0 partner genes should belong to pathways and transcriptional programmes that reflect the tumour phenotype and secondly, there should be a selection for fusion events that shape miRNA expression to benefit the tumour cell through the known hallmarks of cancer. We found that the set of 5 0 partners in miRNA host fusions is non-random, with overrepresentation of highly expressed genes in pathways active in cancer including epithelial-to-mesenchymal transition, translational regulation and oestrogen signalling. Furthermore, many miRNAs were upregulated in samples with host gene fusions, including established oncogenic miRNAs such as mir-21 and the mir-106b~mir-93~mir-25 cluster. To the list of mechanisms for deregulation of miRNA expression, we have added fusion transcripts that change the promoter region. We propose that this adds material for genetic selection and tumour evolution in cancer cells and that miRNA host fusions can act as tumour 'drivers'.

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PEA15 Regulates the DNA Damage-Induced Cell Cycle Checkpoint and Oncogene-Directed Transformation

Cited by 21 publications

References 52 publications

The synthetic retinoid ST1926 as a novel therapeutic agent in rhabdomyosarcoma

The synthetic retinoid ST1926 as a novel therapeutic agent in rhabdomyosarcoma

On the Quest of Cellular Functions of PEA-15 and the Therapeutic Opportunities

Regulatory networks and 5′ partner usage of miRNA host gene fusions in breast cancer

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