The NAB-Brk Signal Bifurcates at JNK to Independently Induce Apoptosis and Compensatory Proliferation

Yaron Suissa,Oren Ziv,Tama Dinur,Eli Arama,Offer Gerlitz

doi:10.1074/jbc.m110.193235

Yaron Suissa, Oren Ziv + Show 3 more

Open Access

https://doi.org/10.1074/jbc.m110.193235

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Abstract

Apoptosis operates to eliminate damaged or potentially dangerous cells. This loss is often compensated by extra proliferation of neighboring cells. Studies in Drosophila imaginal discs suggest that the signal for the additional growth emanates from the dying cells. In particular, it was suggested that the initiator caspase Dronc mediates compensatory proliferation (CP) through Dp53 in wing discs. However, the exact mechanism that governs this CP remained poorly understood. We have previously shown that elimination of misspecified cells due to reduced Dpp signaling is achieved by the interaction of the co-repressor NAB with the transcriptional repressor Brk, which in turn induces Jun N-terminal kinase-dependent apoptosis. Here, we performed a systematic in vivo loss- and gain-of-function analysis to study NAB-induced death and CP. Our findings indicate that the NAB primary signal activates JNK, which in turn transmits two independent signals. One triggers apoptosis through the pro-apoptotic proteins Reaper and Hid, which in turn promote activation of caspases by the apoptosome components Ark and Dronc. The other signal induces CP in a manner that is independent of the death signal, Dronc, or Dp53. Once induced, the apoptotic pathway further activates a CP response. Our data suggest that JNK is the candidate factor that differentiates between apoptosis that involves CP and apoptosis that does not.

Highlights

During development, apoptosis shapes structures by removing excess cells [1]
NAB-induced Apoptosis Is Mediated by the Activators of Apoptosis Rpr and Hid—We recently demonstrated that Drosophila NAB acts as a co-repressor together with Brk to induce apoptosis in cells with impaired Dpp signaling [9]
Recent studies in Drosophila indicated that compensatory proliferation (CP) is triggered by the initiator caspase Dronc through Drosophila p53 (Dp53) during the execution of cell death

Summary

Introduction

Apoptosis shapes structures by removing excess cells [1]. Apoptosis has an important non-developmental role of cellular proofreading: it is used to eliminate misspecified or damaged cells. This cell loss requires the induction of the JNK pathway, which in turn triggers effector caspase activation and apoptosis [9]. One signaling branch triggers apoptosis through induction of two pro-apoptotic proteins, Reaper (Rpr) and Hid. This leads to a reduction in the levels of the major Drosophila inhibitor of apoptosis protein, Diap1, and activation of the apoptosome components Ark and Dronc, which activate the effector caspases and cell

Results

Conclusion