STAT92E is a positive regulator ofDrosophilainhibitor of apoptosis 1 (DIAP/1) and protects against radiation-induced apoptosis

Abstract

The proapoptotic factors Reaper, Hid, Grim, and Sickle regulate apoptosis in Drosophila by inhibiting the antiapoptotic factor DIAP1 (Drosophila inhibitor of apoptosis 1). Heat, UV light, x-rays, and developmental signals can all increase the proapoptotic factors, but the control of transcription of the diap1 gene is unclear. We show that in imaginal discs the single Drosophila STAT protein (STAT92E) when activated can directly increase DIAP1 through binding to STAT DNA-binding sites in the diap1 promoter. The STAT92E contribution to DIAP1 production is required for cell survival after x-irradiation but not under unstressed conditions. Because DIAP1 prevents apoptosis after a variety of stresses, STAT92E may have a role in regulating stress responses in general.Jak STAT ͉ stress ͉ cancer ͉ survival T he regulation of apoptosis is highly conserved in animals and is thought to limit the risk of genomic instability and cancer. Its function depends on the balanced levels of proapoptotic and antiapoptotic proteins (1).The Drosophila proapoptotic factors Reaper, Hid, Grim, and Sickle [also called IAP-binding motif (IBM) proteins] are specifically increased by a variety of agents, both intrinsic developmental signals and extrinsic events (e.g., heat, UV, and ionizing radiation) (2). Inhibition by the IBM proteins of the antiapoptotic activity of DIAP1 (Drosophila inhibitor of apoptosis 1) (3, 4) releases Dronc (the Drosophila caspase 9 ortholog) and drice/dcp1 (caspase 3 ortholog), triggering apoptosis. Proteinprotein interactions of DIAP1 with the IBM proteins and with caspases have received extensive examination (2, 5). However, to our knowledge, direct transcriptional regulation by specific transcription factor(s) of the widely expressed diap1 gene has not been described.Two of the seven human STAT family members are antiapoptotic and their overactivity is correlated with cancer, heightening the previously unrecognized antiapoptotic role of STAT92E. The simpler Jak-STAT pathway in Drosophila consists of the ligands unpaired 1, 2, and 3 and the receptor domeless, with which one Jak family kinase, hopscotch, is associated. Mutations in the pathway affect a wide variety of processes including a positive effect on the cell cycle (6-8).We now report that the full-length tyrosine-phosphorylated STAT92E isoform participates in blocking apoptosis in vivo by acting through highly conserved STAT DNA-binding sites in the diap1 promoter to maintain normal DIAP1 levels. In developing eye and wing discs, STAT92E, although not critical for maintaining basal levels of DIAP1 for survival under unstressed conditions, increases DIAP1 to levels required to combat stressinduced apoptosis.

JAK/STAT autocontrol of ligand-producing cell number through apoptosis

“…In the Drosophila developing wing, phosphorylated Stat92E has been shown to be necessary for protection against stress-induced apoptosis, but not for wing developmental apoptosis (Betz et al, 2008). Here we provide evidence that Upd and the JAK/STAT pathway control developmental apoptosis during Drosophila oogenesis.…”

JAK/STAT signalling mediates cell survival in response to tissue stress

“…So far, only isolated studies have implicated JAK/STAT in cell survival (Betz et al, 2008;Hasan et al, 2015;Guarner et al, 2014;Ohayon et al, 2009). For example, the apoptosis inhibitor IAP has been suggested to be a positively regulated target of Stat92E, protecting cells from apoptosis (Betz et al, 2008;Hasan et al, 2015). We identify the JAK/STAT effector Zfh2 as a potential repressor of kay and hid activity -a molecular pathway expected to restrain excessive JNK-activity and induction of apoptosis (Fig.…”

“…However, continuous overexpression of Upd can also induce apoptosis (not shown) and, thus potentially also sustained JNK-dependent compensatory proliferation, driving tissue growth. So far, only isolated studies have implicated JAK/STAT in cell survival (Betz et al, 2008;Hasan et al, 2015;Guarner et al, 2014;Ohayon et al, 2009). For example, the apoptosis inhibitor IAP has been suggested to be a positively regulated target of Stat92E, protecting cells from apoptosis (Betz et al, 2008;Hasan et al, 2015).…”

“…In fly tumours, STATresponsive enhancers have been mapped (Davie et al, 2015), but few target genes regulating tissue size have been described (Tsai and Sun, 2004;Betz et al, 2008;Hasan et al, 2015). However, several studies suggest that developmental functions of JAK/STAT are mediated by the transcriptional repressors Chinmo (Flaherty et al, 2010), Zfh1 (Ohayon et al, 2009;Leatherman and Dinardo, 2008) and Zfh2 (Perea et al, 2013;Guarner et al, 2014;Ayala-Camargo et al, 2013).…”

Cytokine signaling through the JAK/STAT pathway is required for long-term memory in Drosophila

“…This simplicity makes the Drosophila JAK/STAT pathway an ideal target for loss-offunction studies. Such studies have shown that Drosophila JAK/ STAT signaling is involved in diverse biological processes, including early and late development, innate immunity, germ-cell adhesion, and inhibition of apoptosis (6)(7)(8)(9)(10).…”