The novel function of CD82 and its impact on BCL2L12 via AKT/STAT5 signal pathway in acute myelogenous leukemia cells

Signal transducer and activator of transcription 5 (STAT5) and nucleophosmin (NPM1) are critical regulators of multiple biological and pathological processes. Although a reciprocal regulatory relationship was established between STAT5A and a NPM–ALK fusion protein in T-cell lymphoma, no direct connection between STAT5 and wild-type NPM1 has been documented. Here we demonstrate a mutually regulatory relationship between STAT5 and NPM1. Induction of STAT5 phosphorylation at Y694 (P-STAT5) diminished NPM1 expression, whereas inhibition of STAT5 phosphorylation enhanced NPM1 expression. Conversely, NPM1 not only negatively regulated STAT5 phosphorylation but also preserved unphosphorylated STAT5 level. Mechanistically, we show that NPM1 downregulation by P-STAT5 is mediated by impairing the BRCA1-BARD1 ubiquitin ligase, which controls the stability of NPM1. In turn, decreased NPM1 levels led to suppression of p53 expression, resulting in enhanced cell survival. This study reveals a new STAT5 signaling pathway regulating p53 expression via NPM1 and uncovers new therapeutic targets for anticancer treatment in tumors driven by STAT5 signaling.

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“…These data add to the accumulating evidence that STAT5 regulates the expression of cell survival proteins in cancer cells. 40, 41, 42 …”

Section: Discussionmentioning

confidence: 99%

Phosphorylated STAT5 regulates p53 expression via BRCA1/BARD1-NPM1 and MDM2

et al. 2016

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“…When CD9 and CD82 are expressed, tumor-associated glycoprotein 90K promotes the redifferentiation and apoptosis of colorectal cancer cells [59]. In contrast, CD82 supports the survival of CD34 + / CD38 − AML cells by JAK2/STAT5 signaling-mediated autocrine of IL-10 and expression of anti-apoptotic protein BCL2L12 [27,60].…”

Section: Cell Senescence Cell Proliferation and Cell Survivalmentioning

confidence: 94%

Tetraspanin CD82: a suppressor of solid tumors and a modulator of membrane heterogeneity

Feng

Huang

Wren

et al. 2015

Cancer Metastasis Rev

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Tetraspanin CD82 suppresses the progression and metastasis of a wide range of solid malignant tumors. However, its roles in tumorigenesis and hematopoietic malignancy remain unclear. Ubiquitously expressed CD82 restrains cell migration and cell invasion by modulating both cell-matrix and cell-cell adhesiveness and confining outside-in pro-motility signaling. This restraint at least contributes to, if not determines, the metastasis-suppressive activity and, also likely, the physiological functions of CD82. As a modulator of cell membrane heterogeneity, CD82 alters microdomains, trafficking, and topography of the membrane by changing the membrane molecular landscape. The functional activities of membrane molecules and the cytoskeletal interaction of the cell membrane are subsequently altered, followed by changes in cellular functions. Given its pathological and physiological importance, CD82 is a promising candidate for clinically predicting and blocking tumor progression and metastasis and also an emerging model protein for mechanistically understanding cell membrane organization and heterogeneity.

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“…Previous studies indicate that Bcl2L12 is highly expressed in glioma cells and confers glioma cells the antiapoptotic property. The subsequent reports indicate that Bcl2L12 is also expressed by other cancer cells, such as leukemia, bladder cancer, and breast cancer . The Bcl2L12 is not only expressed by cancer cells, others found that Bcl2L12 was also expressed in vascular endothelial cells, is associated with cirrhosis, and is involved in immune dysregulation .…”

Section: Discussionmentioning

confidence: 99%

B cell lymphoma‐2‐like protein‐12 association with T‐helper 2 inflammation in chronic rhinosinusitis with allergy

Zeng

et al. 2018

Int Forum Allergy Rhinol

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Background: T-helper 2 (Th2) polarization plays a critical role in the pathogenesis of chronic rhinosinusitis (CRS) with accompanying nasal allergy. Recent studies indicate that B cell lymphoma-2-like protein-12 (Bcl2L12) is associated with immune dysregulation. The purpose of this study was to elucidate the role of Bcl2L12 in the pathogenesis of Th2 polarization of CRS patients.Methods: CRS patients with nasal allergy (CRSa) and without nasal allergy (CRSna) were recruited into this study. CD4 + T cells were isolated from the blood samples of human subjects. A variety of immunologic molecular strategies were used to assess Th2 polarization and Bcl2L12 expression.Results: Twenty CRSa patients, 20 CRSna patients, and 20 healthy subjects were recruited into this study. High levels of immunoglobulin E (IgE), interleukin 4 (IL-4), IL-5, IL-13, and Bcl2L12 were detected in nasal extracts of CRSa patients, but not in CRSna patients. The levels of Bcl2L12 were positively correlated with Th2 cytokines. CD4 + T cells from CRSa patients were prone to differentiate into Th2 cells, in which Bcl2L12 was required. Conclusion:Bcl2L12 is positively correlated with Th2 cytokine levels in the nasal mucosa of CRSa patients. Bcl2L12 contributes to the Th2 polarization, which may be a novel therapeutic target in the treatment of CRSa. C 2018 ARS-AAOA, LLC.

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The novel function of CD82 and its impact on BCL2L12 via AKT/STAT5 signal pathway in acute myelogenous leukemia cells

Cited by 27 publications

References 42 publications

Phosphorylated STAT5 regulates p53 expression via BRCA1/BARD1-NPM1 and MDM2

Phosphorylated STAT5 regulates p53 expression via BRCA1/BARD1-NPM1 and MDM2

Tetraspanin CD82: a suppressor of solid tumors and a modulator of membrane heterogeneity

B cell lymphoma‐2‐like protein‐12 association with T‐helper 2 inflammation in chronic rhinosinusitis with allergy

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