Proviral integration site 2 is required for interleukin‐6 expression induced by interleukin‐1, tumour necrosis factor‐α and lipopolysaccharide

Yang, Jianfei; Li, Xiang; Hanidu, Adedayo; Htut, Tin M.; Sellati, Rosemarie; Wang, Lian; Jiang, Huiping; Li, Jun

doi:10.1111/j.1365-2567.2010.03286.x

Cited by 11 publications

(14 citation statements)

References 35 publications

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“…12 However, PIM2 has been shown to be required for interleukin 6 expression, which is regulated at least in part by STAT5. 14,15 These data suggest that PIM kinases may augment STAT5 activity through a feed-forward mechanism to maximally amplify the STAT5 proliferative signal. In the responder KG1 cell line, STAT5A/B is required for regulating CD25 mRNA expression, as knockdown of STAT5A/B significantly repressed the mRNA levels of CD25 ( Figure 3Fi) and resulted in a marked decrease of CD25 protein levels ( Figure 3Fii).…”

Section: Identification Of Aml Cell Lines Sensitive To the Inhibitionmentioning

confidence: 95%

“…Nevertheless, the fact that STAT5 activation induces interleukin 6 gene transcription, and that PIM2 has been shown to be required for interleukin 6 expression, implies that a PIM family-mediated feed-forward mechanism regulating STAT activity may exist. 14,15 The PIM serine/threonine kinase family is composed of 3 highly homologous proteins: PIM1, PIM2, and PIM3. Functional redundancy of the 3 PIM kinases has previously been demonstrated both in vitro and in vivo.…”

Section: Introductionmentioning

confidence: 99%

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PIM inhibitors target CD25-positive AML cells through concomitant suppression of STAT5 activation and degradation of MYC oncogene

Guo

Wang

Zhang

et al. 2014

Blood

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Key Points• CD25 is a predictive biomarker for sensitivity to PIM inhibitors in AML cells.• PIM inhibitors may prolong overall/relapse-free survival through attenuating STAT5 activation and destabilizing MYC in CD25 1 AML cells.Postchemotherapy relapse presents a major unmet medical need in acute myeloid leukemia (AML), where treatment options are limited. CD25 is a leukemic stem cell marker and a conspicuous prognostic marker for overall/relapse-free survival in AML. Rare occurrence of genetic alterations among PIM family members imposes a substantial hurdle in formulating a compelling patient stratification strategy for the clinical development of selective PIM inhibitors in cancer. Here we show that CD25, a bona fide STAT5 regulated gene, is a mechanistically relevant predictive biomarker for sensitivity to PIM kinase inhibitors. Alone or in combination with tyrosine kinase inhibitors, PIM inhibitors can suppress STAT5 activation and significantly shorten the half-life of MYC to achieve substantial growth inhibition of high CD25-expressing AML cells. Our results highlight the importance of STAT5 and MYC in rendering cancer cells sensitive to PIM inhibitors. Because the presence of a CD25-positive subpopulation in leukemic blasts correlates with poor overall or relapse-free survival, our data suggest that a combination of PIM inhibitors with chemotherapy and tyrosine kinase inhibitors could improve long-term therapeutic outcomes in

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Section: Identification Of Aml Cell Lines Sensitive To the Inhibitionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

PIM inhibitors target CD25-positive AML cells through concomitant suppression of STAT5 activation and degradation of MYC oncogene

Guo

Wang

Zhang

et al. 2014

Blood

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“…cDNA synthesis and TaqMan Real Time PCR were performed as described previously (25)(26)(27). TaqMan quantitative PCR was performed on a 7900HT Real Time PCR System (Applied Biosystems).…”

Section: Rna Extraction Quantitative Rt-pcrmentioning

confidence: 99%

Pharmacologic Inhibition of RORγt Regulates Th17 Signature Gene Expression and Suppresses Cutaneous Inflammation In Vivo

Skepner¹,

Ramesh²,

Trocha³

et al. 2014

The Journal of Immunology

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132

123

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IL-17–producing CD4+Th17 cells, CD8+Tc17 cells, and γδ T cells play critical roles in the pathogenesis of autoimmune psoriasis. RORγt is required for the differentiation of Th17 cells and expression of IL-17. In this article, we describe a novel, potent, and selective RORγt inverse agonist (TMP778), and its inactive diastereomer (TMP776). This chemistry, for the first time to our knowledge, provides a unique and powerful set of tools to probe RORγt-dependent functions. TMP778, but not TMP776, blocked human Th17 and Tc17 cell differentiation and also acutely modulated IL-17A production and inflammatory Th17-signature gene expression (Il17a, Il17f, Il22, Il26, Ccr6, and Il23) in mature human Th17 effector/memory T cells. In addition, TMP778, but not TMP776, inhibited IL-17A production in both human and mouse γδ T cells. IL-23–induced IL-17A production was also blocked by TMP778 treatment. In vivo targeting of RORγt in mice via TMP778 administration reduced imiquimod-induced psoriasis-like cutaneous inflammation. Further, TMP778 selectively regulated Th17-signature gene expression in mononuclear cells isolated from both the blood and affected skin of psoriasis patients. In summary, to our knowledge, we are the first to demonstrate that RORγt inverse agonists: 1) inhibit Tc17 cell differentiation, as well as IL-17 production by γδ T cells and CD8+ Tc17 cells; 2) block imiquimod-induced cutaneous inflammation; 3) inhibit Th17 signature gene expression by cells isolated from psoriatic patient samples; and 4) block IL-23–induced IL-17A expression. Thus, RORγt is a tractable drug target for the treatment of cutaneous inflammatory disorders, which may afford additional therapeutic benefit over existing modalities that target only IL-17A.

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“…PIM2 was first discovered in lymphomas in mice and found to have anti-apoptotic effects as well as several other functions including cell cycle regulation, cell proliferation, and transcriptional activity [2,[4][5][6][7][8]. Several studies have demonstrated that PIM2 plays an important role in cell survival and apoptosis in tumors [9][10][11][12].…”

Section: Introductionmentioning

confidence: 98%

Effects of low doses of Tat-PIM2 protein against hippocampal neuronal cell survival

Woo

Shin

Kim

et al. 2015

Journal of the Neurological Sciences

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Proviral integration site 2 is required for interleukin‐6 expression induced by interleukin‐1, tumour necrosis factor‐α and lipopolysaccharide

Cited by 11 publications

References 35 publications

PIM inhibitors target CD25-positive AML cells through concomitant suppression of STAT5 activation and degradation of MYC oncogene

PIM inhibitors target CD25-positive AML cells through concomitant suppression of STAT5 activation and degradation of MYC oncogene

Pharmacologic Inhibition of RORγt Regulates Th17 Signature Gene Expression and Suppresses Cutaneous Inflammation In Vivo

Effects of low doses of Tat-PIM2 protein against hippocampal neuronal cell survival

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