Abstract
The term programmed cell death (PCD) was coined in 1965 to describe the loss of the intersegmental muscles (ISMs) of moths at the end of metamorphosis. While it was subsequently demonstrated that this hormonally controlled death requires de novo gene expression, the signal transduction pathway that couples hormone action to cell death is largely unknown. Using the ISMs from the tobacco hawkmoth Manduca sexta, we have found that Acheron/LARP6 mRNA is induced ∼1,000-fold on the day the muscles become committed to die. Acheron functions as a survival protein that protects cells until cell death is initiated at eclosion (emergence), at which point it becomes phosphorylated and degraded in response to the peptide Eclosion Hormone (EH). Acheron binds to a novel BH3-only protein that we have named BBH1 (BAD/BNIP3 homology 1). BBH1 accumulates on the day the ISMs become committed to die and is presumably liberated when Acheron is degraded. This is correlated with the release and rapid degradation of cytochrome c and the subsequent demise of the cell. RNAi experiments in the fruit fly Drosophila confirmed that loss of Acheron results in precocious ecdysial muscle death while targeting BBH1 prevents death altogether. Acheron is highly expressed in neurons and muscles in humans and drives metastatic processes in some cancers, suggesting that it may represent a novel survival protein that protects terminally differentiated cells and some cancers from death.
Highlights
All cells express the genetic machinery required to commit suicide, a process known as programmed cell death (PCD)
In support of the hypothesis that Acheron is degraded in a cyclic guanosine monophosphate (cGMP)-dependent manner, we examined the expression of the Eclosion Hormone (EH) Receptor (EHR), a guanylate cyclase related to the atrial natriuretic membrane receptor (Schwartz and Truman, 1984; Chang et al, 2009)
We propose that the expression and subsequent degradation of Acheron is the essential upstream regulatory event that controls intersegmental muscles (ISMs) loss
Summary
All cells express the genetic machinery required to commit suicide, a process known as programmed cell death (PCD). Control of Programmed Cell Death innervate (Hamburger, 1975). It can sculpt portions of the body, for example when parallel rows of cells die in the developing limb bud to free up the digits (Lorda-Diez et al, 2015). Cell death can remove deleterious cells, such as self-reactive thymocytes during negative selection in the thymus (McPhee et al, 1979). It can recycle obsolete tissues such as the tadpole tail during amphibian metamorphosis (Ishizuya-Oka, 2011). It has been estimated that misregulation of cell death may contribute to 70% of human diseases (Reed, 2002)
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