<scp>PIM</scp>2 interacts with tristetraprolin and promotes breast cancer tumorigenesis

Ren, Chune; Yang, Tingting; Qiao, Pengyun; Wang, Li; Han, Xue; Lv, Shijun; Sun, Yonghong; Liu, Zhijun; Du, Yu; Yu, Zhenhai

doi:10.1002/1878-0261.12192

Cited by 28 publications

(24 citation statements)

References 35 publications

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“…The cells were seeded onto six-well plates at a concentration of 200 cells in 2 ml culture medium per well and cultured at 37 °C and 5% CO 2 for 12–14 days. Cells were fixed by 4% paraformaldehyde, and then treated with crystal violet staining solution, and cells were photographed [ 28 ]. For wound healing assay, cells were cultured in six-well plates till a monolayer was formed.…”

Section: Methodsmentioning

confidence: 99%

PIM2-mediated phosphorylation of hexokinase 2 is critical for tumor growth and paclitaxel resistance in breast cancer

et al. 2018

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Hexokinase-II (HK2) is a key enzyme involved in glycolysis, which is required for breast cancer progression. However, the underlying post-translational mechanisms of HK2 activity are poorly understood. Here, we showed that Proviral Insertion in Murine Lymphomas 2 (PIM2) directly bound to HK2 and phosphorylated HK2 on Thr473. Biochemical analyses demonstrated that phosphorylated HK2 Thr473 promoted its protein stability through the chaperone-mediated autophagy (CMA) pathway, and the levels of PIM2 and pThr473-HK2 proteins were positively correlated with each other in human breast cancer. Furthermore, phosphorylation of HK2 on Thr473 increased HK2 enzyme activity and glycolysis, and enhanced glucose starvation-induced autophagy. As a result, phosphorylated HK2 Thr473 promoted breast cancer cell growth in vitro and in vivo. Interestingly, PIM2 kinase inhibitor SMI-4a could abrogate the effects of phosphorylated HK2 Thr473 on paclitaxel resistance in vitro and in vivo. Taken together, our findings indicated that PIM2 was a novel regulator of HK2, and suggested a new strategy to treat breast cancer.

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Section: Methodsmentioning

confidence: 99%

PIM2-mediated phosphorylation of hexokinase 2 is critical for tumor growth and paclitaxel resistance in breast cancer

et al. 2018

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“…Furthermore, we used immunofluorescent staining to determine endogenous PIM2 was colocalized with endogenous FBP1 primarily in the nucleus but also slightly in the cytoplasm (Figure 1 F). To determine which domains of PIM2 and FBP1 are responsible for regulating this interaction, truncated constructs of the functional domains of PIM2 and FBP1 were made for further analysis (Figure 1 G and 1 I) 5 , 22 . Co-IP analyses suggested that the kinase domain of PIM2 (33-286aa) was associated with FBP1 (Figure 1 H).…”

Section: Resultsmentioning

confidence: 99%

“…Moreover, various special inhibitors, including JP11646, SMI-4a and SGI-1776, have been developed for PIM kinase activity and have been used for clinical treatment 19 - 21 . Recently, we found that PIM2 acts as an oncogene in breast cancer 15 , 17 , 22 , but the underlying mechanism of its oncogene function remains largely unknown.…”

Section: Introductionmentioning

confidence: 99%

Fructose-1, 6-bisphosphatase 1 interacts with NF-κB p65 to regulate breast tumorigenesis via PIM2 induced phosphorylation

Lü¹,

Ren²,

Yang³

et al. 2020

Theranostics

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Rationale: Fructose-1, 6-bisphosphatase 1 (FBP1), a rate-limiting enzyme in gluconeogenesis, was recently shown to be a tumor suppressor and could mediate the activities of multiple transcriptional factors via its non-canonical functions. However, the underlying mechanism of posttranscriptional modification on the non-canonical functions of FBP1 remains elusive. Methods: We employed immunoaffinity purification to identify binding partner(s) and used co-immunoprecipitation to verify their interactions. Kinase reaction was used to confirm PIM2 could phosphorylate FBP1. Overexpression or knockdown proteins were used to assess the role in modulating p65 protein stability. Mechanistic analysis was involved in protein degradation and polyubiquitination assays. Nude mice and PIM2-knockout mice was used to study protein functions in vitro and in vivo . Results: Here, we identified Proviral Insertion in Murine Lymphomas 2 (PIM2) as a new binding partner of FBP1, which could phosphorylate FBP1 on Ser144. Surprisingly, phosphorylated FBP1 Ser144 abrogated its interaction with NF-κB p65, promoting its protein stability through the CHIP-mediated proteasome pathway. Furthermore, phosphorylation of FBP1 on Ser144 increased p65 regulated PD-L1 expression. As a result, phosphorylation of FBP1 on Ser144 promoted breast tumor growth in vitro and in vivo . Moreover, the levels of PIM2 and pSer144-FBP1 proteins were positively correlated with each other in human breast cancer and PIM2 knockout mice. Conclusions: Our findings revealed that phosphorylation noncanonical FBP1 by PIM2 was a novel regulator of NF-κB pathway, and highlights PIM2 inhibitors as breast cancer therapeutics.

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“…ZFP36 was a downregulated gene in BC, and upregulation of ZFP36 inhibited transactivation of ERα, cell proliferation, as well as the capacity to form new tumors 18,30 . It was noted that circRNAs played critical functions during tumor progression by binding to miRs and miRs affected behaviors of malignant cells by regulating posttranscriptional gene expression 11,31 .…”

Section: Discussionmentioning

confidence: 99%

“…The bioinformatics website miR.org identified zinc finger protein 36 (ZFP36) as a target gene of miR‐182. As an AU‐rich element‐binding protein, ZFP36 was poorly expressed in BC, and low‐expressed ZFP36 was associated with poor patient survival 18 . Moreover, in BC, ZFP36 was reported to suppress cell proliferation in vitro and inhibit tumor growth in vivo by activating cell cycle arrest at the S phase 19 …”

Section: Introductionmentioning

confidence: 99%

Circular RNA 000554 represses epithelial‐mesenchymal transition in breast cancer by regulating microRNA‐182/ZFP36 axis

Mao

Cao

et al. 2020

FASEB j.

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Increasing evidence indicates that circular RNAs (circRNAs) play a crucial role in regulating microRNAs (miRs) and mRNAs during breast cancer (BC) progression. Based on the in silico analysis of circRNA/miR/mRNA in BC, we aim to define an important role of circRNA_000554 in BC in relation to miR‐182 and zinc finger protein 36 (ZFP36). Low expression of circRNA_000554 and ZFP36, and high miR‐182 expression were determined in the clinical BC tissues. CircRNA_000554 acted as a sponge of miR‐182, and miR‐182 directly targeted ZFP36. After that, in order to evaluate the effects of circRNA_000554, miR‐182, and ZFP36 on cellular process, we evaluated in vitro epithelial‐mesenchymal transition (EMT) and in vivo tumor growth after delivering a series of overexpression plasmids, mimic, inhibitor, or shRNAs into BC cells. Increasing circRNA_000554 suppressed EMT, cell invasion and migration during BC by depleting miR‐182 and increasing ZFP36. The inhibitory effect of circRNA_000554 on tumor growth was validated in vivo. Taken together, the present study confirms that circRNA_000554 functioned as an inhibitor of EMT in BC and suggests a molecular mechanism that circRNA_000554 bound to miR‐182 to upregulate ZFP36 in this process.

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PIM2 interacts with tristetraprolin and promotes breast cancer tumorigenesis

Cited by 28 publications

References 35 publications

PIM2-mediated phosphorylation of hexokinase 2 is critical for tumor growth and paclitaxel resistance in breast cancer

PIM2-mediated phosphorylation of hexokinase 2 is critical for tumor growth and paclitaxel resistance in breast cancer

Fructose-1, 6-bisphosphatase 1 interacts with NF-κB p65 to regulate breast tumorigenesis via PIM2 induced phosphorylation

Circular RNA 000554 represses epithelial‐mesenchymal transition in breast cancer by regulating microRNA‐182/ZFP36 axis

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