NEDD4-2-dependent control of Na+ homeostasis and renal disease

Manning, James A.; Henshall, Tanya L.; Kumar, Sharad

doi:10.1080/15384101.2017.1386514

Cited by 18 publications

(14 citation statements)

References 7 publications

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“…LncRNA ZFAS1 expression is upregulated in CRC, and upregulated ZFAS1 is correlated with advanced TNM stage, poor overall survival, and lymph nodes metastasis of CRC patients. 16 Likewise, we found that LINC00346 overexpression was closely correlated with a decreased survival rate in CRC patients, and was positive associated with TNM stage and lymphatic metastasis. These results suggest that LINC00346 may be a potential prognostic factor for CRC.…”

Section: Discussionmentioning

confidence: 54%

“…Emerging evidence has proved that some lncRNAs are upregulated in CRC, such as PANDAR, 15 MALAT1, 6 and ZFAS1. 16 LINC00346 has been found to be upregulated in CRC and increased the WBSCR22 expression via inhibiting miR-509-5p. 17 LINC00346 is recurrently amplified and high-expressed in gastric cancer, and its expression is positively correlated with poor prognosis.…”

Section: Discussionmentioning

confidence: 99%

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Silencing of lncRNA LINC00346 Inhibits the Proliferation and Promotes the Apoptosis of Colorectal Cancer Cells Through Inhibiting JAK1/STAT3 Signaling

Li¹,

Wen²

2020

CMAR

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The study was aimed to investigate the effect and mechanism of lncRNA LINC00346 on cell proliferation and apoptosis of colorectal cancer (CRC). Methods: The expression of lncRNA LINC00346 in CRC tissues and cells was detected by qRT-PCR. LINC00346 was overexpressed and silenced in HT29 and LoVo cells by the transfection of pcDNA-LINC00346 and si-LINC00346. The proliferation of CRC cells was detected by CCK-8 and colony-formation assay. The apoptosis was detected by flow cytometry assay. The expression of apoptosis-associated proteins (Caspase-3, Bcl-2, Bax) and JAK1/STAT3 signaling-associated proteins (JAK1, STAT3, p-JAK1, p-STAT3) was detected by Western blot. The tumor growth was detected in mice subcutaneous injected with transfected HT29 cells. Results: LINC00346 was significantly upregulated in CRC tissues and cells. Overexpression of LINC00346 significantly increased the OD 450 values, number of colonies, decreased the apoptosis rate, upregulated Bcl-2, and downregulated Caspase-3 and Bax in HT29 and LoVo cells. Knockdown of LINC00346 exerted opposite results of proliferation and apoptosis on HT29 and LoVo cells. The expression levels of JAK1/JAK1 and p-STAT3/STAT3 were upregulated by LINC00346 overexpression. Tofacitinib (JAK1 inhibitor) reversed the tumorpromoting effect of LINC00346 overexpression on CRC cells. In vivo experiments further validated that LINC00346 overexpression promoted the growth of CRC xenograft tumors. Conclusion: LncRNA LINC00346 promoted the proliferation and inhibited the apoptosis of CRC cells through activating JAK1/STAT3 signaling.

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Section: Discussionmentioning

confidence: 54%

Section: Discussionmentioning

confidence: 99%

Silencing of lncRNA LINC00346 Inhibits the Proliferation and Promotes the Apoptosis of Colorectal Cancer Cells Through Inhibiting JAK1/STAT3 Signaling

Li¹,

Wen²

2020

CMAR

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“…Identifying compounds with the appropriate CDK inhibitory profile to maximize effects on transcription, cell cycle and cancer cell death, while retaining sufficient selectivity to avoid unwanted collateral toxicities, is challenging. Due to its essential nature, inhibition of CDK1 appears not to be desirable [39].…”

Section: Kinome Profilingmentioning

confidence: 99%

Fadraciclib (CYC065), a novel CDK inhibitor, targets key pro-survival and oncogenic pathways in cancer

et al. 2020

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Cyclin-dependent kinases (CDKs) contribute to the cancer hallmarks of uncontrolled proliferation and increased survival. As a result, over the last two decades substantial efforts have been directed towards identification and development of pharmaceutical CDK inhibitors. Insights into the biological consequences of CDK inhibition in specific tumor types have led to the successful development of CDK4/6 inhibitors as treatments for certain types of breast cancer. More recently, a new generation of pharmaceutical inhibitors of CDK enzymes that regulate the transcription of key oncogenic and pro-survival proteins, including CDK9, have entered clinical development. Here, we provide the first disclosure of the chemical structure of fadraciclib (CYC065), a CDK inhibitor and clinical candidate designed by further optimization from the aminopurine scaffold of seliciclib. We describe its synthesis and mechanistic characterization. Fadraciclib exhibits improved potency and selectivity for CDK2 and CDK9 compared to seliciclib, and also displays high selectivity across the kinome. We show that the mechanism of action of fadraciclib is consistent with potent inhibition of CDK9-mediated transcription, decreasing levels of RNA polymerase II C-terminal domain serine 2 phosphorylation, the prosurvival protein Myeloid Cell Leukemia 1 (MCL1) and MYC oncoprotein, and inducing rapid apoptosis in cancer cells. This cellular potency and mechanism of action translate to promising anti-cancer activity in human leukemia mouse xenograft models. Studies of leukemia cell line sensitivity identify mixed lineage leukemia (MLL) gene status and the level of B-cell lymphoma 2 (BCL2) family proteins as potential markers for selection of patients with greater sensitivity to fadraciclib. We show that the combination of fadraciclib with BCL2 inhibitors, including venetoclax, is synergistic in leukemic cell models, as predicted from simultaneous inhibition of MCL1 and BCL2 pro-survival pathways. Fadraciclib preclinical pharmacology data support its therapeutic potential in CDK9-or CDK2-dependent cancers and as a rational combination with BCL2 inhibitors in hematological malignancies. Fadraciclib is currently in Phase 1 clinical studies in patients with advanced solid tumors (NCT02552953) and also in combination with venetoclax in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) (NCT03739554) and relapsed refractory acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) (NCT04017546).

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“…Pol η is about 10,000 times (error rate of ∼1/100) more error-prone than Pol δ or Pol ɛ when replicating normal templates, typified by the signature mutations of A to G or C to T transitions under certain sequence contexts ( Chen and Sugiyama, 2017 , Matsuda et al., 2001 ). Both types of mutations have been observed in a number of recently identified cancer mutational signatures ( Rogozin et al., 2018 , Rubin and Green, 2009 , Supek and Lehner, 2017 ). Thus, it is prohibitive for unregulated participation of Pol η in routine DNA replication, a process that demands an error rate of less than one in a billion.…”

Section: Introductionmentioning

confidence: 99%

Phosphorylation Alters the Properties of Pol η: Implications for Translesion Synthesis

et al. 2018

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SummaryThere are significant ambiguities regarding how DNA polymerase η is recruited to DNA lesion sites in stressed cells while avoiding normal replication forks in non-stressed cells. Even less is known about the mechanisms responsible for Pol η-induced mutations in cancer genomes. We show that there are two safeguards to prevent Pol η from adventitious participation in normal DNA replication. These include sequestration by a partner protein and low basal activity. Upon cellular UV irradiation, phosphorylation enables Pol η to be released from sequestration by PDIP38 and activates its polymerase function through increased affinity toward monoubiquitinated proliferating cell nuclear antigen (Ub-PCNA). Moreover, the high-affinity binding of phosphorylated Pol η to Ub-PCNA limits its subsequent displacement by Pol δ. Consequently, activated Pol η replicates DNA beyond the lesion site and potentially introduces clusters of mutations due to its low fidelity. This mechanism could account for the prevalence of Pol η signatures in cancer genome.

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NEDD4-2-dependent control of Na⁺ homeostasis and renal disease

Cited by 18 publications

References 7 publications

<p>Silencing of lncRNA LINC00346 Inhibits the Proliferation and Promotes the Apoptosis of Colorectal Cancer Cells Through Inhibiting JAK1/STAT3 Signaling</p>

<p>Silencing of lncRNA LINC00346 Inhibits the Proliferation and Promotes the Apoptosis of Colorectal Cancer Cells Through Inhibiting JAK1/STAT3 Signaling</p>

Fadraciclib (CYC065), a novel CDK inhibitor, targets key pro-survival and oncogenic pathways in cancer

Phosphorylation Alters the Properties of Pol η: Implications for Translesion Synthesis

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