Esophageal cancer-related gene 4 is a secreted inducer of cell senescence expressed by aged CNS precursor cells

Abstract

Mammalian aging is thought to be partially caused by the diminished capacity of stem/precursor cells to undergo self-renewing divisions. Although many cell-cycle regulators are involved in this process, it is unknown to what extent cell senescence, first identified as irreversible growth arrest in vitro, contributes to the aging process. Here, using a serum-induced mouse oligodendrocyte precursor cell (mOPC) senescence model, we identified esophageal cancer-related gene 4 (Ecrg4) as a senescence inducer with implications for the senescence-like state of postmitotic cells in the aging brain. Although mOPCs could proliferate indefinitely when cultured using the appropriate medium (OPC medium), they became senescent in the presence of serum and maintained their senescent phenotype even when the serum was subsequently replaced by OPC medium. We show that Ecrg4 was up-regulated in the senescent OPCs, its overexpression in OPCs induced senescence by accelerating the proteasome-dependent degradation of cyclins D1 and D3, and that its knockdown by a specific short hairpin RNA prevented these phenotypes. We also show that senescent OPCs secreted Ecrg4 and that recombinant Ecrg4 induced OPC senescence in culture. Moreover, increased Ecrg4 expression was observed in the OPCs and neural precursor cells in the aged mouse brain; this was accompanied by the expression of senescence-associated β-galactosidase activity, indicating the cells' entrance into senescence. These results suggest that Ecrg4 is a factor linking neural-cell senescence and aging.cyclin D1 and D3 | neural precursor cells | oligodendrocyte precursor cells | retinoblastoma | senescence-associated β-galactosidase

Soluble purified recombinant C2ORF40 protein inhibits esophageal cancer cell proliferation by inducing cell cycle G1 phase block

“…Cell cycle analysis was performed by flow cytometry, and the result suggested that rhC2ORF40 could arrest the ESCC cells at the G 1 /S checkpoint and delay the transition of the cell cycle into the S phase (Table I), which was consistent with our previous C2ORF40 gene transfection result (4). Consequently, rhC2ORF40 protein slowed down cell cycle progression, and caused cell cycle G 1 phase block.…”

miR340 Suppresses the Stem-like Cell Function of Glioma-Initiating Cells by Targeting Tissue Plasminogen Activator

“…Cellular senescence can inhibit tumor formation by modulating the redox state in CSCs and by regulating p27 in glioma cells (26,27). In addition, GICs derived from wild-type mice expressing the senescence-promoting factor esophageal cancer-related gene 4 (Ecrg4) caused significantly reduced tumor formation in mouse brains compared with cells from Ecrg4-knockdown mice (28). We observed that miR340 overexpression in hGICs decreased DNA methyltransferase 1 (DNMT1) expression ( Supplementary Fig.…”

Early Life Stress Inhibits Expression of a Novel Innate Immune Pathway in the Developing Hippocampus

“…Fourth, additional work is needed to validate more genes found on the array and examine their role in mediating some of the developmental effects of BDS. For example, three of the five most highly regulated genes found on the array are genes that regulate neural stem cell proliferation and survival (eg, ECRG, Kujuro et al, 2010;ENPP2, Koike et al, 2011;SOSTDC1, Lintern et al, 2009), providing a possible molecular explanation for the reduced DNA content seen in the hippocampus of pups exposed to BDS (Wei et al, 2010). Finally, our data does not allow us to assess the exact contribution that a decrease in LBP expression in the hippocampus has in the behavioral sequelae of animals exposed to BDS, nor do we imply that all the behavioral consequences of BDS are mediated by its ability to inhibit expression of LBP.…”