Persengiev, S. | bioRxiv Science

bioRxiv2017

A Mechanism of ATF5 Anti-Apoptotic Action that Promotes Leukemia Cells Survival

ATF5 transcription factor was found to play an essential role in hematopoietic cell survival and neuronal cell differentiation. Pro-survival activities of ATF5 are believed to be a result of its ability to inhibit apoptosis. Anti-apoptotic function of ATF5 is almost certainly carried out by regulating gene transcription, but information concerning its target genes has been missing. Here, we report the identification of cyclin D3 as an essential target of ATF5, and provide evidence that its upregulation is critical for the realization of ATF5-induced inhibition of apoptosis. Functional analysis confirmed the association of cyclin D3 with leukemia cells resistance to apoptosis and ATF5-induced splenic dysplasia in transgenic mice. These data link cyclin D3 cell cycle regulatory functions with the apoptotic machinery and reveal a potentially important facet of ATF5 biology.

cancer biology↗

bioRxiv2017

Identification of an Essential IL15-STAT1-IRX3 Prosurvival Pathway in T Lymphocytes with Therapeutic Implications

IRX3 homeobox transcription factor plays a role in neural development and in the pathogenesis of obesity and insulin resistance. T lymphocytes play an essential role in the pathogenesis of obesity and their expansion and differentiation is a tightly controlled process. Circulating cytokines trough activation of cell death mechanisms controls the number of CD4 and CD8 T cells, and failure to activate apoptosis is considered the main cause for their uncontrolled expansion. Here, the identification an essential anti-apoptotic pathway in T lymphocytes is presented, whereby IL-15 activation of Stat/Jak signaling cascade leads to induction of the IRX3 expression. IRX3, in turn, promotes T cells survival and self-renewal, at least partially, by controlling the expression of T-bet transcription factor eomesodermin (EOMES). The Stat/Jak signaling inhibition by Jak inhibitor 1 suppresses IRX3 transcription in T lymphocytes and tumor cell lines and increases apoptosis after growth factor deprivation. Our results demonstrate that IRX3 is essential in T lymphocytes differentiation and reveal that the IL-15-dependent IRX3 pro-survival pathway provides potential therapeutic target for regulation of T cell proliferation that has implications for immune cell malignancies, obesity and autoimmune diseases.

molecular biology↗