Genomics

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MiRNA Microarray analysis of TNFα induced senescence in Human umbilical vein endothelial cells


ABSTRACT: Cellular senescence is a key cell-fate program that leads to an essentially irreversible proliferative arrest in potentially damaged cells. Cytokine production and signaling play a significant role in senescence. Tumor necrosis factor-alpha (TNFα), an important pro-inflammatory cytokine secreted by some senescent cells, can induce senescence in mouse and human cells. However, downstream signaling pathways and key regulatory genes linking inflammation to senescence are not fully characterized. Using human umbilical vein endothelial cells (HUVECs) as a model, we show TNFα induces permanent growth arrest and increased senescence markers such as p21, p16, and senescence-associated β-galactosidase (SA-β-gal), accompanied by persistent DNA damage and ROS. By gene expression profiling and pathway analysis, we identify the crucial involvement of inflammatory networks, an interferon signature, and persistent activation of the Janus kinase (JAK) /signal transducer and activator of transcription (STAT) pathway in TNFα-mediated senescence. TNFα initiates a STAT-dependent autocrine loop leading to sustained inflammation, DNA damage, and expression of interferon response genes to lock cells into senescence. Further, we show STAT1/3 activation is necessary for cytokine and ROS production during TNFα-induced senescence. However, inhibition of STAT1/3 did not rescue cells from TNFα-mediated senescence. Rather, blockade of STAT activation accelerated senescence, suppressed genes that control the cell cycle, and modulated TNFα-induced senescence. Our findings suggest a positive feedback mechanism via a STAT pathway that sustains cytokine production and reveal a reciprocal regulatory role of JAK/STAT in TNFα-mediated senescence.

ORGANISM(S): synthetic construct Homo sapiens

PROVIDER: GSE92655 | GEO | 2017/03/10

SECONDARY ACCESSION(S): PRJNA358247

REPOSITORIES: GEO

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