ETV6

Transcription factor ETV6 (ETS translocation variant 6) (ETS-related protein Tel1) (Tel) [TEL] [TEL1]

Publications

FOXO1 and ETV6 genes may represent novel regulators of splicing factor expression in cellular senescence.

PubMed

Full text

Cellular plasticity is a key facet of cellular homeostasis requiring correct temporal and spatial patterns of alternative splicing. Splicing factors, which orchestrate this process, demonstrate age-related dysregulation of expression; they are emerging as potential influences on aging and longevity. The upstream drivers of these alterations are still unclear but may involve aberrant cellular signaling. We compared the phosphorylation status of proteins in multiple signaling pathways in early and late passage human primary fibroblasts. We then assessed the impact of chemical inhibition or targeted knockdown of direct downstream targets of the ERK and AKT pathways on splicing factor expression, cellular senescence, and proliferation kinetics in senescent primary human fibroblasts. Components of the ERK and AKT signaling pathways demonstrated altered activation during cellular aging. Inhibition of AKT and ERK pathways led to up-regulation of splicing factor expression, reduction in senescent cell load, and partial reversal of multiple cellular senescence phenotypes in a dose-dependent manner. Furthermore, targeted knockdown of the genes encoding the downstream targets FOXO1 or ETV6 was sufficient to mimic these observations. Our results suggest that age-associated dysregulation of splicing factor expression and cellular senescence may derive in part from altered activity of ERK and AKT signaling and may act in part through the ETV6 and FOXO1 transcription factors. Targeting the activity of downstream effectors of ERK and AKT may therefore represent promising targets for future therapeutic intervention.-Latorre, E., Ostler, E. L., Faragher, R. G. A., Harries, L. W. FOXO1 and ETV6 genes may represent novel regulators of splicing factor expression in cellular senescence.

MeSH Terms

• Cell Proliferation
• Cells, Cultured
• Cellular Senescence
• Fibroblasts
• Forkhead Box Protein O1
• Humans
• Phosphatidylinositol 3-Kinases
• Phosphorylation
• Protein Kinases
• Proto-Oncogene Proteins c-ets
• RNA Splicing Factors
• Repressor Proteins
• Signal Transduction

Keywords

• AKT
• ERK
• aging
• fibroblasts
• signaling