Dataset Information

Microarray analysis revealing common and distinct functions of promyelocytic leukemia protein (PML) and tumor necrosis factor alpha (TNF?) signaling in endothelial cells.

ABSTRACT: Promyelocytic leukemia protein (PML) is a tumor suppressor that is highly expressed in endothelial cells nonetheless its role in endothelial cell biology remains elusive. Tumor necrosis factor alpha (TNF?) is an important cytokine associated with many inflammation-related diseases. We have previously demonstrated that TNF? induces PML protein accumulation. We hypothesized that PML may play a role in TNF? signaling pathway. To identify potential PML target genes and investigate the putative crosstalk between PML's function and TNF? signaling in endothelial cells, we carried out a microarray analysis in human primary umbilical endothelial cells (HUVECs).We found that PML and TNF? regulate common and distinct genes involved in a similar spectrum of biological processes, pathways and human diseases. More importantly, we found that PML is required for fine-tuning of TNF?-mediated immune and inflammatory responses. Furthermore, our data suggest that PML and TNF? synergistically regulate cell adhesion by engaging multiple molecular mechanisms. Our biological functional assays exemplified that adhesion of U937 human leukocytes to HUVECs is co-regulated by PML and TNF? signaling.Together, our study identified PML as an essential regulator of TNF? signaling by revealing the crosstalk between PML knockdown-mediated effects and TNF?-elicited signaling, thereby providing novel insights into TNF? signaling in endothelial cells.

SUBMITTER: Cheng X

PROVIDER: S-EPMC3542097 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature

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Microarray analysis revealing common and distinct functions of promyelocytic leukemia protein (PML) and tumor necrosis factor alpha (TNFα) signaling in endothelial cells.

Cheng Xiwen X Kao Hung-Ying HY

BMC genomics 20120904

<h4>Background</h4>Promyelocytic leukemia protein (PML) is a tumor suppressor that is highly expressed in endothelial cells nonetheless its role in endothelial cell biology remains elusive. Tumor necrosis factor alpha (TNFα) is an important cytokine associated with many inflammation-related diseases. We have previously demonstrated that TNFα induces PML protein accumulation. We hypothesized that PML may play a role in TNFα signaling pathway. To identify potential PML target genes and investigate ...[more]

PMID: 22947142

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Project description:Dysregulation of PML, a significant tumor suppressor is linked with cancers of different histological origins, with a decreased expression observed with a higher tumor grade. This necessitates studying the mechanisms to maintain a stable expression of PML. However much less is known about the transcriptional regulation of PML, more so in the context of breast carcinoma. ERβ has emerged as a critical factor in understanding breast cancer, especially since a huge proportion of breast cancers are ERα- and thus insensitive to tamoxifen therapy. This study aims to uncover an unidentified mechanism of PML gene regulation and its stabilization in breast cancer via ERβ signalling and the impact on cellular apoptosis. We found that clinical expression of PML positively correlates with that of ERβ both in normal and breast carcinoma samples and inversely correlates with markers of cellular proliferation, hinting towards a possible mechanistic interdependence. Both mRNA and protein expression of PML were increased in response to ERβ overexpression on multiple human breast cancer cell lines. Mechanistically, luciferase reporter assays and chromatin-immunoprecipitation assays demonstrated that ERβ can interact with the PML promoter via ERE and AP1 sites to enhance its transcription. ERβ induced stable PML expression causes a decline of its target protein Survivin and simultaneously provides a stable docking platform leading to stabilisation of its target Foxo3a, further causing transcriptional upregulation of pro-apoptotic factors p21 and p27. Immunohistochemical analyses of cancer and normal breast tissues and functional assays conducted corroborated the findings. Collectively, our study identifies ERβ signalling as a novel mechanism for PML gene regulation in ERα- breast cancer. It also reveals bi-directional downstream effect in which 'ERβ-PML-(Foxo3a/Survivin)' network acts as a therapeutic axis by suppressing cellular survival and promoting cellular apoptosis in breast carcinoma.

Dataset Information

Microarray analysis revealing common and distinct functions of promyelocytic leukemia protein (PML) and tumor necrosis factor alpha (TNF?) signaling in endothelial cells.

Publications

Microarray analysis revealing common and distinct functions of promyelocytic leukemia protein (PML) and tumor necrosis factor alpha (TNFα) signaling in endothelial cells.

Similar Datasets

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