PTEN-mediated ERK1/2 inhibition and paradoxical cellular proliferation following Pnck overexpression

Deb, Tushar B.; Barndt, Robert J.; Zuo, Annie; Sengupta, Surojeet; Coticchia, Christine M.; Johnson, Michael D.

doi:10.4161/cc.27837

Cited by 7 publications

(4 citation statements)

References 34 publications

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“…Among those genes, Mapk1 and Pten were also among the 31 predicted targets for miR-132 binding (ESM Table 5). Notably, Mapk1 , also known as Erk2 , is a serine-threonine kinase located downstream of the tumor-suppressor phosphatase Pten and both genes play a critical role in the control of cell proliferation and survival [29,30]. We then used dual luciferase assays to test whether miR-132 -mediated downregulation of Mapk1 and Pten occurs through a direct binding of miR-132 to their mRNA 3′-UTR.…”

Section: Resultsmentioning

confidence: 99%

MiR-132 controls pancreatic beta cell proliferation and survival through Pten/Akt/Foxo3 signaling

Mziaut

Henniger

Ganss

et al. 2020

Molecular Metabolism

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ObjectiveMicroRNAs (miRNAs) play an integral role in maintaining beta cell function and identity. Deciphering their targets and precise role, however, remains challenging. In this study, we aimed to identify miRNAs and their downstream targets involved in the regeneration of islet beta cells following partial pancreatectomy in mice.MethodsRNA from laser capture microdissected (LCM) islets of partially pancreatectomized and sham-operated mice were profiled with microarrays to identify putative miRNAs implicated in beta cell regeneration. Altered expression of the selected miRNAs, including miR-132, was verified by RT-PCR. Potential targets of miR-132 were selected through bioinformatic data mining. Predicted miR-132 targets were validated for their changed RNA, protein expression levels, and signaling upon miR-132 knockdown and/or overexpression in mouse MIN6 and human EndoC-βH1 insulinoma cells. The ability of miR-132 to foster beta cell proliferation in vivo was further assessed in pancreatectomized miR-132−/− and control mice.ResultsPartial pancreatectomy significantly increased the number of BrdU+/insulin+ islet cells. Microarray profiling revealed that 14 miRNAs, including miR-132 and -141, were significantly upregulated in the LCM islets of the partially pancreatectomized mice compared to the LCM islets of the control mice. In the same comparison, miR-760 was the only downregulated miRNA. The changed expression of these miRNAs in the islets of the partially pancreatectomized mice was confirmed by RT-PCR only in the case of miR-132 and -141. Based on previous knowledge of its function, we focused our attention on miR-132. Downregulation of miR-132 reduced the proliferation of MIN6 cells while enhancing the levels of pro-apoptotic cleaved caspase-9. The opposite was observed in miR-132 overexpressing MIN6 cells. Microarray profiling, RT-PCR, and immunoblotting of the latter cells demonstrated their downregulated expression of Pten with concomitant increased levels of pro-proliferative factors phospho-Akt and phospho-Creb and inactivation of pro-apoptotic Foxo3a via its phosphorylation. Downregulation of Pten was further confirmed in the LCM islets of pancreatectomized mice compared to the sham-operated mice. Moreover, overexpression of miR-132 correlated with increased proliferation of EndoC-βH1 cells. The regeneration of beta cells following partial pancreatectomy was lower in the miR-132/212−/− mice than the control littermates.ConclusionsThis study provides compelling evidence about the critical role of miR-132 for the regeneration of mouse islet beta cells through the downregulation of its target Pten. Hence, the miR-132/Pten/Akt/Foxo3 signaling pathway may represent a suitable target to enhance beta cell mass.

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Section: Resultsmentioning

confidence: 99%

MiR-132 controls pancreatic beta cell proliferation and survival through Pten/Akt/Foxo3 signaling

Mziaut

Henniger

Ganss

et al. 2020

Molecular Metabolism

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“…In addition, high expression of PNCK is reported in clear cell renal cell carcinoma (ccRCC), which is correlated with shorter overall survival, an independent prognostic factor for survival in ccRCC 14. Recently, studies have revealed that PNCK induces ligand-independent EGFR degradation by probable perturbation of the Hsp90 chaperone complex, representing an attractive target in EGFR-regulated oncogenesis 15-17. Additionally, ectopic expression of PNCK causes trastuzumab resistance in HER-2 amplified breast cancer via PTEN-mediated process, suggesting that inhibition of PNCK may be a novel strategy to overcome drug resistance 18.…”

Section: Discussionmentioning

confidence: 99%

PNCK depletion inhibits proliferation and induces apoptosis of human nasopharyngeal carcinoma cells in vitro and in vivo

Xu¹,

Wang²,

Cai³

et al. 2019

J. Cancer

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Purpose: Recent studies indicate that pregnancy upregulated non-ubiquitous calmodulin kinase (PNCK) is significantly up-regulated in breast and renal carcinomas. However, the expression profile and its biological relevance of PNCK in nasopharyngeal carcinoma (NPC) have not been elucidated.Methods: The expression level of PNCK was detected in specimens of NPC (n=10) and normal tissues (n=10) by real-time PCR and immunohistochemistry. Celigo Cell Counting and MTT assay were used to measure cell viability. Apoptosis was detected by flow cytometric analysis and caspases 3/7 activity assay. Real-time PCR and Western blotting were performed to evaluate the expression of PNCK. The bioluminescence imaging was used to evaluate the effects of PNCK knockdown on tumor growth using a xenograft animal model. The global gene expression profile was determined in wild type and PNCK-depleted CNE-2 cells via transcriptomics analysis. For mechanical investigation, the changes of PI3K/AKT/mTOR signaling pathway were detected by Western blotting.Results: The mRNA and protein levels of PNCK were increased in human NPC samples. In vitro experiments showed that shRNA or CRISPR-Cas9 mediated silencing of PNCK inhibited proliferation and induced apoptosis in NPC cells. In addition, in vivo assay revealed that knockdown of PNCK suppressed tumor growth. Consistently, a significant reduction of tumor bioluminescence in mice inoculated with PNCK-knockdown cells compared to that of control cells. In gene expression, the transcriptomics analysis revealed that there were 589 upregulated genes and 589 downregulated genes in PNCK-knockdown cells. Ingenuity Pathway Analysis (IPA) identified significant changes of PI3K/AKT/mTOR signaling pathway in PNCK-knockdown cells. Furthermore, western blot analysis revealed that interference with PNCK reduced the phosphorylation levels of PI3K, AKT and mTOR in CNE-2 cells.Conclusion: This study for the first time demonstrates that knockdown of PNCK could suppress growth and induce apoptosis of NPC cells both in vitro and in vivo by regulating PI3K/AKT/mTOR signaling pathway. These findings suggest that PNCK might be a novel therapeutic target for NPC treatment.

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“…Pnck, a calmodulin kinase highly overexpressed in renal and breast carcinoma, inhibits serum-induced ERK1/2 and p38 MAPK activity, inducing a strong proliferative capacity in the cells. Introduction of wt-PTEN or its protein phosphatase active but lipid phosphatase dead mutant enhances Pnck-mediated-ERK1/2 inhibition, causing further proliferation [ 79 ]. Cellular stress results in p38 MAPK-mediated induction of Pnck expression that further increases PTEN’s protein phosphatase activity.…”

Section: Ptenmentioning

confidence: 99%

Tumor Suppressors Having Oncogenic Functions: The Double Agents

Datta

Chakraborty

Basu³

et al. 2020

Cells

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Cancer progression involves multiple genetic and epigenetic events, which involve gain-of-functions of oncogenes and loss-of-functions of tumor suppressor genes. Classical tumor suppressor genes are recessive in nature, anti-proliferative, and frequently found inactivated or mutated in cancers. However, extensive research over the last few years have elucidated that certain tumor suppressor genes do not conform to these standard definitions and might act as “double agents”, playing contrasting roles in vivo in cells, where either due to haploinsufficiency, epigenetic hypermethylation, or due to involvement with multiple genetic and oncogenic events, they play an enhanced proliferative role and facilitate the pathogenesis of cancer. This review discusses and highlights some of these exceptions; the genetic events, cellular contexts, and mechanisms by which four important tumor suppressors—pRb, PTEN, FOXO, and PML display their oncogenic potentials and pro-survival traits in cancer.

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PTEN-mediated ERK1/2 inhibition and paradoxical cellular proliferation following Pnck overexpression

Cited by 7 publications

References 34 publications

MiR-132 controls pancreatic beta cell proliferation and survival through Pten/Akt/Foxo3 signaling

MiR-132 controls pancreatic beta cell proliferation and survival through Pten/Akt/Foxo3 signaling

PNCK depletion inhibits proliferation and induces apoptosis of human nasopharyngeal carcinoma cells in vitro and in vivo

Tumor Suppressors Having Oncogenic Functions: The Double Agents

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