The Tumor Suppressor Rb Critically Regulates Starvation-Induced Stress Response in C. elegans

Abstract

Summary How animals coordinate gene expression in response to starvation is an outstanding problem closely linked to aging, obesity, and cancer [1–5]. Newly hatched Caenorhabditis elegans respond to food deprivation by halting development and promoting long-term survival (L1 diapause), thereby providing an excellent model to study starvation response [2, 6, 7]. Through a genetic search, we have discovered that the tumor suppressor Rb critically promotes survival during L1 diapause and likely does so by regulating the expression of genes in both insulin-IGF-1 signaling (IIS)-dependent and -independent pathways mainly in neurons and the intestine. Global gene expression analyses suggested that Rb maintains the “starvation-induced transcriptome” and represses the “re-feeding induced transcriptome”, including the repression of many pathogen/toxin/oxidative stress-inducible and metabolic genes, as well as the activation of many other stress-resistant genes, mitochondrial respiratory chain genes, and potential IIS receptor antagonists. Notably, the majority of genes dysregulated in starved L1 Rb(−) animals were not found to be dysregulated in fed conditions. Together, these findings identify Rb as a critical regulator of the starvation response and suggest a link between functions of tumor suppressors and starvation survival. These results may provide mechanistic insights into why cancer cells are often hypersensitive to starvation treatment.

Starvation-Induced Stress Response Is Critically Impacted by Ceramide Levels in Caenorhabditis elegans

“…To understand the role of ceramide in regulating animal starvation survival, we screened all available, viable, C. elegans mutants in the ceramide metabolism pathways for altered L1 starvation survival rates (Cui et al 2013) ( Figure 1A and Table S1), and found many such mutants were significantly short-lived during L1 starvation ( Figure 1, A-C, Figure S1, A-C, and Table S1). Specifically, animals with mutations in the de novo ceramide biosynthesis pathway were sensitive to starvation-induced stress ( Figure 1, B-C and Table S1).…”

“…The L1 starvation assay was done following the protocol described previously (Lee and Ashrafi 2008;Cui et al 2013;Zhang et al 2011b). Survival curves were drawn based on three or more independent experiments.…”

“…(1) Two classes of daf-16-responsive genes were reported in Tepper et al (2013). (2) lin-35/Rb regulated genes during L1 starvation were reported in Cui et al (2013). (3) The FedUP and StarvUP gene lists obtained from www.wormbase.org were originally submitted by R. Baugh based on the published paper (Baugh et al 2009) (http:// www.wormbase.org/species/c_elegans/expression_cluster/ WBPaper00032948:FedUp#0154-10; http://www.wormbase.…”

“…A transient receptor potential vanilloid (TRPV) channel and microRNAs were shown to modulate L1 diapause by regulatand Avery 2009). We previously reported that tumor suppressor Rb critically impacts survival during L1 diapause by promoting the starvation-induced transcriptome, and repressing the refeeding induced transcriptome (Cui et al 2013), which affect the activity of multiple regulatory pathways. Identifying and analyzing new factors involved in the process continues to be important for us to understand how different signals and regulatory pathways coordinately promote longterm survival of animals in response to starvation.…”

AMPK blocks starvation-inducible transgenerational defects in Caenorhabditis elegans

“…How this information is transduced to affect gene expression in response to a given stimulus is currently speculative at best. During starvation in C. elegans L1 larvae, a specific geneexpression program is initiated (46) and during this period RNA polymerase II is observed in different configurations: in the "docked" state RNA polymerase II is on proximal promoters waiting for cues to initiate, whereas in the "paused" configuration the complex remains in a postinitiated state, presumably on hold until a physiological or developmental contingency is satisfied (47,48). This developmental pausing is not exceptional and in many organisms RNA polymerase II is maintained in a postinitiated state where subsequent elongation is regulated by factors that associate with the phosphorylated carboxyl-terminal domain of the RNA polymerase II large subunit (49).…”