JNK-dependent cell cycle stalling in G2 promotes survival and senescence-like phenotypes in tissue stress

Abstract

The restoration of homeostasis after tissue damage relies on proper spatial-temporal control of damage-induced apoptosis and compensatory proliferation. In Drosophila imaginal discs these processes are coordinated by the stress response pathway JNK. We demonstrate that JNK signaling induces a dose-dependent extension of G2 in tissue damage and tumors, resulting in either transient stalling or a prolonged but reversible cell cycle arrest. G2-stalling is mediated by downregulation of the G2/M-specific phosphatase String(Stg)/Cdc25. Ectopic expression of stg is sufficient to suppress G2-stalling and reveals roles for stalling in survival, proliferation and paracrine signaling. G2-stalling protects cells from JNK-induced apoptosis, but under chronic conditions, reduces proliferative potential of JNK-signaling cells while promoting non-autonomous proliferation. Thus, transient cell cycle stalling in G2 has key roles in wound healing but becomes detrimental upon chronic JNK overstimulation, with important implications for chronic wound healing pathologies or tumorigenic transformation.

Two-Faced: Roles of JNK Signalling During Tumourigenesis in the Drosophila Model

“…In these cells, ROS production and p53 upregulation contribute to the activation of JNK signalling, which then induces Upd1/Upd2/Upd3 expression and secretion, leading to non-autonomous tissue growth effects (Figure 4C; Nakamura et al, 2014). A somewhat related role for JNK signalling was recently observed for cells upon wounding in wing imaginal discs -wounding induced JNK signalling, and cells became transiently "stalled" in the cell cycle at G2 phase (or near-permanently "arrested" in G2 phase after JNK induction via egr overexpression in the rotund expression domain) (Cosolo et al, 2019). Researchers found that JNK signalling induces G2 phase stalling/arrest via downregulating the activity of Stg (an inducer of mitosis) and, furthermore, that cells with this G2 profile were protected from JNK-mediated apoptosis (Cosolo et al, 2019).…”

“…A somewhat related role for JNK signalling was recently observed for cells upon wounding in wing imaginal discs -wounding induced JNK signalling, and cells became transiently "stalled" in the cell cycle at G2 phase (or near-permanently "arrested" in G2 phase after JNK induction via egr overexpression in the rotund expression domain) (Cosolo et al, 2019). Researchers found that JNK signalling induces G2 phase stalling/arrest via downregulating the activity of Stg (an inducer of mitosis) and, furthermore, that cells with this G2 profile were protected from JNK-mediated apoptosis (Cosolo et al, 2019). It was also shown that the G2-biased profile of clones mutant for wts or dlg1 was due to JNK signalling (Cosolo et al, 2019).…”

“…Researchers found that JNK signalling induces G2 phase stalling/arrest via downregulating the activity of Stg (an inducer of mitosis) and, furthermore, that cells with this G2 profile were protected from JNK-mediated apoptosis (Cosolo et al, 2019). It was also shown that the G2-biased profile of clones mutant for wts or dlg1 was due to JNK signalling (Cosolo et al, 2019). Interestingly, the wildtype tissue adjacent to these mutant clones overgrows, and was suggested by researchers to be another example of JNK-induced non-autonomous tissue growth (Cosolo et al, 2019).…”

“…It was also shown that the G2-biased profile of clones mutant for wts or dlg1 was due to JNK signalling (Cosolo et al, 2019). Interestingly, the wildtype tissue adjacent to these mutant clones overgrows, and was suggested by researchers to be another example of JNK-induced non-autonomous tissue growth (Cosolo et al, 2019). Similar cell cycle arrest has also been observed in wholly scrib −/− wing imaginal disc tumours -strong JNK signalling in periphery cells early in tumourigenesis induces G2/M phase arrest, but JNK signalling decreases over time in these cells and, together with a concomitant increase in Ras-MAPK signalling, the cell cycle arrest ceases and the tumours overgrow (Ji et al, 2019).…”

Overexpression of Krüppel-Like Factor 4 Suppresses Migration and Invasion of Non-Small Cell Lung Cancer Through c-Jun-NH2-Terminal Kinase/Epithelial-Mesenchymal Transition Signaling Pathway

“…The JNK MAPK pathway is involved in many cellular processes, such as cell growth, differentiation, migration, apoptosis, and inflammatory and immune responses. It has also been implicated in many pathological conditions, including cancer, stroke, heart disease, and inflammatory disease (Coffey, 2014;Yuan et al, 2017;Blum et al, 2019;Cosolo et al, 2019). Studies show that JNK plays a vital role in the whole metastatic process.…”