Telomeric repeat-binding factor 2-interacting protein 1 (TERF2-interacting telomeric protein 1) (TRF2-interacting telomeric protein 1) (Dopamine receptor-interacting protein 5) (Repressor/activator protein 1 homolog) (RAP1 homolog) (hRap1) [DRIP5] [RAP1] [PP8000]
Disturbed flow (d-flow)-induced senescence and activation of endothelial cells (ECs) have been suggested to have critical roles in promoting atherosclerosis. Telomeric repeat-binding factor 2 (TERF2)-interacting protein ([[TERF2IP]]), a member of the shelterin complex at the telomere, regulates the senescence-associated secretory phenotype (SASP), in which EC activation and senescence are engendered simultaneously by p90RSK-induced phosphorylation of [[TERF2IP]] S205 and subsequent nuclear export of the [[TERF2IP]]-TERF2 complex. In this study, we investigated [[TERF2IP]]-dependent gene expression and its role in regulating d-flow-induced SASP. A principal component analysis and hierarchical clustering were used to identify genes whose expression is regulated by [[TERF2IP]] in ECs under d-flow conditions. Senescence was determined by reduced telomere length, increased p53 and p21 expression, and increased apoptosis; EC activation was detected by NF-κB activation and the expression of adhesion molecules. The involvement of [[TERF2IP]] S205 phosphorylation in d-flow-induced SASP was assessed by depletion of [[TERF2IP]] and mutation of the phosphorylation site. Our unbiased transcriptome analysis showed that [[TERF2IP]] caused alteration in the expression of a distinct set of genes, including rapamycin-insensitive companion of mTOR (RICTOR) and makorin-1 (MKRN1) ubiquitin E3 ligase, under d-flow conditions. In particular, both depletion of [[TERF2IP]] and overexpression of the [[TERF2IP]] S205A phosphorylation site mutant in ECs increased the d-flow and p90RSK-induced MKRN1 expression and subsequently inhibited apoptosis, telomere shortening, and NF-κB activation in ECs via suppression of p53, p21, and telomerase (TERT) induction. MKRN1 and RICTOR belong to a distinct reciprocal gene set that is both negatively and positively regulated by p90RSK. [[TERF2IP]] S205 phosphorylation, a downstream event of p90RSK activation, uniquely inhibits MKRN1 expression and contributes to EC activation and senescence, which are key events for atherogenesis.
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