Targeting Dysregulated Cell Cycle and Apoptosis for Polycystic Kidney Disease Therapy

Ibraghimov‐Beskrovnaya, Oxana

doi:10.4161/cc.6.7.4047

Cited by 31 publications

(23 citation statements)

References 37 publications

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“…Roscovitine has also been extensively studied in animal models and is undergoing phase II human studies for polycystic kidney disease (11,39,44,58), non-small-cell lung cancer, and breast cancer (13,16,18,23,27,30,50,65,67,75). Over 3 days in the HTS or subsequent assays, roscovitine at 3.6, 11, and 33 M inhibited EBNA1 and oriPCp-dependent FL reporter activity by ϳ15%, ϳ35%, and ϳ80%, respectively, and had a minimal or no effect on EBNA1-independent SV40p-RL activity (Fig.…”

Section: Resultsmentioning

confidence: 99%

Roscovitine Inhibits EBNA1 Serine 393 Phosphorylation, Nuclear Localization, Transcription, and Episome Maintenance

Kang

Lee

Soni

et al. 2011

J Virol

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Latent Epstein-Barr virus (EBV) infection causes human lymphomas and carcinomas. EBV usually persists asan episome in malignant cells. EBV episome persistence, replication, and gene expression are dependent on EBNA1 binding to multiple cognate sites in oriP. To search for inhibitors of EBNA1-and oriP-dependent episome maintenance or transcription, a library of 40,550 small molecules was screened for compounds that inhibit EBNA1-and oriP-dependent transcription and do not inhibit EBNA1-and oriP-independent transcription. This screening identified roscovitine, a selective inhibitor of cyclin-dependent kinase 1 (CDK1), CDK2, CDK5, and CDK7. Based on motif predictions of EBNA1 serine 393 as a CDK phosphorylation site and 486 RALL 489 and 580 KDLVM 584 as potential cyclin binding domains, we hypothesized that cyclin binding to EBNA1 may enable CDK1, -2, -5, or -7 to phosphorylate serine 393. We found that Escherichia coli-expressed EBNA1 amino acids 387 to 641 were phosphorylated in vitro by CDK1-, -2-, -5-, and -7/cyclin complexes and serine 393 phosphorylation was roscovitine inhibited. Further, S393A mutation abrogated phosphorylation. S393A mutant EBNA1 was deficient in supporting EBNA1-and oriP-dependent transcription and episome persistence, and roscovitine had little further effect on the diminished S393A mutant EBNA1-mediated transcription or episome persistence. Immunoprecipitated FLAG-EBNA1 was phosphorylated in vitro, and roscovitine inhibited this phosphorylation. Moreover, roscovitine decreased nuclear EBNA1 and often increased cytoplasmic EBNA1, whereas S393A mutant EBNA1 was localized equally in the nucleus and cytoplasm and was unaffected by roscovitine treatment. These data indicate that roscovitine effects are serine 393 specific and that serine 393 is important in EBNA1-and oriPCp-dependent transcription and episome persistence.Epstein-Barr virus (EBV) replicates in oropharyngeal epithelial cells (62,70,85). Subsequent latent infection of mature B lymphocytes can result in infectious mononucleosis and is essential for long-term latency and reactivation and continues to be shed in saliva (21). Latently EBV-infected B cells can emerge as Burkitt's lymphomas (BL) or Hodgkin's disease in otherwise healthy people or as lymphoproliferative disease in people who have T-lymphocyte deficiencies due to HIV infection, transplantation, advanced age, or a genetic predisposition (4,8,25,34,49,62,85). In immunocompetent people, particularly those of southern Chinese descent, latent EBV infection can also cause nasopharyngeal carcinoma, which is the most common EBV malignancy worldwide (25,34). Latent EBV infection is a significant cause of morbidity and mortality.In latent infections, including malignancies, EBV usually persists as a multicopy episome (1,47,56,60). EBV genome integration is unusual (33, 52). EBNA1 is essential for EBV episome persistence in dividing cells and enhances episome transcription (59,61,83). The EBNA1 DNA binding domain recognizes 24 cognate sites in the EBV episome OriP element, while ...

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Section: Resultsmentioning

confidence: 99%

Roscovitine Inhibits EBNA1 Serine 393 Phosphorylation, Nuclear Localization, Transcription, and Episome Maintenance

Kang

Lee

Soni

et al. 2011

J Virol

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“…In addition, these authors mentioned that AQP-4 is increased in GBL and plays a significant role in GBL cell migration and invasion, in addition to its well-known function in brain edema (31). The inhibitory effect of ROSC on AQP-2 was shown in kidneys (32). In the present study, IM decreased AQP-4 levels; however, the combination group and ROSC increased AQP-4 levels in T98G GBL cells.…”

Section: Discussionmentioning

confidence: 45%

Imatinib mesylate decreases the cytotoxic effect of roscovitine on human glioblastoma cells in vitro and the role of midkine

et al. 2011

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Abstract. The purpose of the present study was to overcome resistance to imatinib (IM) by combining it with roscovitine (ROSC) and to investigate whether or not midkine (MK) had an effect on this combination in the treatment of glioblastoma (GBL). Human T98 GBL cells were used to evaluate the effects of IM (10 µM), ROSC (200 µM) and their combination on the cell proliferation index, apoptotic index, the apoptotic protein and anti-apoptotic protein levels, and ultrastructure. All applications decreased the cell proliferation index and increased the apoptotic index, but ROSC was the most efficient drug and the second most efficient drug was IM. Notably, ROSC increased anti-apoptotic proteins levels (PDGFR-α, AQP-4, hTERT), COX-1 activity and ribosome numbers. The effects of ROSC on hTERT, MK, AQP-4 and MRP-1 levels and COX-1 activity were reported for the first time. ROSC induced the highest increase in caspase-3 levels. Autophagy was not involved in the activity of ROSC in GBL spheroids. The combination of IM with ROSC showed an antagonist effect in the treatment of human GBL cells. The combination group decreased certain anti-apoptotic protein levels (PDGFR-α, EGFR, p-gp, MRP-1 and MK), cAMP levels, COX-1 activity and apoptotic protein levels (caspase-3). However, it induced the highest increase in hTERT levels and COX-2 activity. Ribosome numbers were much lower than those in the ROSC group and no autophagic vacuole was observed. In conclusion, more investigations are required to identify the key regulatory components that are responsible for this antagonism; however, the determination of this combination therapy as a failure therapy may be precautionary for oncologists in the treatment of GBL patients and potentially may contribute to the efficacy of new therapeutic regimens.

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“…Because of long-lasting effects of cdk-inhibitors, they may only need to be used periodically [28], potentially making their use in treating PKD more feasible. Treatment with roscovitine also caused an increase in cystic epithelial differentiation back toward normal suggestive that it was acting on basic epithelial abnormalities associated with HRFC disease [29]. However, there are no human clinical trials at this time with roscovitine or any other cdk-inhibitor.…”

Section: Vascular Endothelial Growth Factor (Vegf)mentioning

confidence: 99%

Novel Therapies for Polycystic Kidney Disease

Gattone¹,

Bacallao²

2011

J Genet Syndr Gene Ther

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Targeting Dysregulated Cell Cycle and Apoptosis for Polycystic Kidney Disease Therapy

Cited by 31 publications

References 37 publications

Roscovitine Inhibits EBNA1 Serine 393 Phosphorylation, Nuclear Localization, Transcription, and Episome Maintenance

Roscovitine Inhibits EBNA1 Serine 393 Phosphorylation, Nuclear Localization, Transcription, and Episome Maintenance

Imatinib mesylate decreases the cytotoxic effect of roscovitine on human glioblastoma cells in vitro and the role of midkine

Novel Therapies for Polycystic Kidney Disease

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