The regulation of both metabolism and the cell cycle has been intensely studied for decades due to their central roles in the etiology and progression of human disease. In the 1920s, Otto Warburg observed that cancerous tissues metabolize glucose at a much higher rate than normal tissue due to an increased rate of glycolysis. Since that discovery, numerous genetic and environmental factors associated with cancer progression have been linked to changes in cell metabolism.1 An understanding of how cancerous cells bypass normal growth control mechanisms may be achieved through investigation of the crosstalk between metabolism and cell cycle regulation. Research in model systems such as C. elegans provides a foundation for understanding these crosstalk mechanisms. C. elegans possesses unique characteristics useful for phenotypic and genetic analyses, including a semi-transparent body that allows for direct visualization of cells at all developmental stages, established forward and reverse genetics methods and a streamlined genome that displays low redundancy while maintaining high conservation within specific gene families.2 Perhaps the most useful characteristic for cell cycle analyses is the highly reproducible cell lineage that is subject to change only in response to genetic alteration or environmental distress.
C. elegans develops through a highly reproducible somatic cell lineage,2,3 which suggests a high degree of spatiotemporal coordination between cell division, apoptosis, cell fate specification and differentiation.4-7 In contrast to the embryo that enjoys the protection of the eggshell and is generally considered self-sufficient, the developing larvae must find a source of food if it is to survive and develop into a fertile adult. At two stages, C. elegans larvae are able to sense environmental cues, such as temperature, crowding and nutrition, and adapt their developmental programs to better suit ambient conditions.8 Immediately after hatching, the larvae make a developmental decision to proceed with post-embryonic development based on the availability of food.9-11 Indeed, the ability to arrest post-embryonic development immediately after hatching in response to food deprivation, a state termed L1 diapause, and to resume larval development in response to food availability is experimentally exploited to generate large populations of synchronously developing larvae.12 Similarly, upon exposure to unfavorable growth conditions during early larval development, the animals can adopt an alternate developmental program called the dauer stage.8,13 Both of these developmental states are characterized by arrested cell cycles; however, the key distinguishing feature is that during dauer arrest, the larvae enter an alternative developmental program suited to withstand stressful conditions, while L1 diapause is simply a temporary arrest of larval development.13 Studies to delineate the developmental mechanisms used to regulate the cell cycle are uncovering an elaborate system of checks and balances that, together, ensure cell cycle progression occurs under the appropriate conditions and at the appropriate time.5,14 Since the components and mechanisms involved in the cell cycle and its regulation are generally conserved with higher organisms, including humans, these studies are invaluable for understanding the molecular basis of and developing treatments for a wide variety of diseases.
Completion of a cell cycle carries a high energetic cost, thus the ability of a cell to sense its energy status and influence cell cycle progression is important for survival. Two important energy-sensing pathways, AMP-activated protein kinase (AMPK) and insulin/IGF-1 signaling have been well characterized in C. elegans in the context of aging, dauer formation and, more recently, cell cycle progression (Fig. 1). Specifically, these pathways have been implicated in controlling two separate cell cycle processes: G1/S progression in somatic cells and G2/M progression in the germ line. In this review, we discuss how these signaling pathways sense energy availability and override the genetically scheduled cell cycle to arrest cell divisions until conditions are favorable for further growth and development. In addition, pathways involved in oxygen sensing have been shown to regulate cell cycles in C. elegans; this suspended animation is discussed elsewhere in this issue by Padilla and Ladage.
Figure 1. Induction of cell cycle quiescence by starvation. Hypothetical models incorporating AMPK and insulin/IGF-1 signaling during (A) L1 diapause and (B) dauer arrest to arrest cell divisions. Please see text for details.
Insulin/IGF-1 signaling plays a vital role in initiating post-embryonic development of the newly hatched larvae. Specifically, in response to starvation, components of the insulin/IGF-1 pathway mediate a G1-phase arrest of somatic cells during L1 diapause.38 Based on the examination of several cell lineages, wild-type animals arrest cell divisions during L1 diapause, while animals deficient in daf-16/FOXO activity fail to arrest the cell cycle.38 Accordingly, animals lacking the opposing daf-2 activity display a heightened sensitivity to food deprivation.38 These findings establish that insulin signaling is an important contributor to nutrient-dependent G1 cell cycle arrest in C. elegans. Further, the failure of daf-16/FOXO mutant animals to arrest cell divisions correlates with a failure to accumulate CKI-1/p27kip1, suggesting that insulin/IGF-1 signaling controls L1 diapause arrest through the promotion of cyclin-dependent kinase inhibitory activity.38 These results are supported by data obtained in other experimental systems demonstrating that FOXO transcription factors can regulate cell cycle progression through control of p27kip1.41-43 Although inactivation of daf-16/FOXO results in failure to accumulate CKI-1/p27kip1 in C. elegans, further studies are needed to establish the precise mechanism of daf-16-mediated cell cycle arrest.
In addition to a role in starvation-induced G1 arrest of somatic cells, insulin/IGF-1 signaling also mediates an arrest at the G2/M transition in germ cells.10,39,44 Analyses of animals lacking the p27kip1-related G1/S inhibitor encoded by cki-1 revealed over proliferation of a wide variety of somatic cell types,11 but obvious hyperproliferation was not observed within the germ line.44 This observation suggests that regulation of germ cell divisions does not occur at the G1/S transition as in the somatic tissues.10 While primordial germ cells do, in fact, arrest cell cycles during L1 diapause, the cells arrest with 4N DNA content and duplicated centrosomes, indicating that the arrest occurs after completion of S phase.10 Similar to somatic cells, the germline cell cycle arrest in L1 diapause is dependent on components of the insulin/IGF-1 signaling pathway. Loss-of-function (lf) mutation within daf-18/PTEN allows germ cells to inappropriately proliferate during L1 diapause.10 The failure of germ cells to arrest in daf-18/PTEN(lf) mutant animals is due to overactive insulin/IGF-1 signaling, since further loss of the genetically opposing insulin/IGF-1 signaling components, such as age-1 or akt-1, suppress the hyperproliferation defect.10 Interestingly, daf-16 function is not required for germ cell arrest during L1 diapause.10 Since the proposed cell cycle quiescence function of DAF-16/FOXO is to promote expression of the G1/S inhibitor CKI-1,38 daf-16 function may be dispensable in organizing the G2/M arrest of the germ cells. This suggests that the germline L1 diapause arrest may involve a non-canonical insulin/IGF-1 pathway that diverges prior to the activity of the canonical downstream effector, DAF-16/FOXO.
The requirement for insulin/IGF-1 signaling in germ cell arrest is not limited to L1 diapause, as insulin signaling components are also necessary for germ cell arrest during the dauer stage. At this stage, gain-of-function (gf) mutation of akt-1 or daf-18(lf) disrupts the ability of germline cells to arrest proliferation during the dauer stage.39 In contrast to L1 diapause, daf‑16/FOXO activity appears to be required in the germ line for dauer stage proliferation arrest.39 The differential requirement may reflect inherent differences between the mechanisms used to arrest germ cells during L1 and dauer stages. Despite these differences, it is clear that components of the insulin/IGF-1 signaling pathway play an indispensible role in sensing the low nutrient conditions and temporarily halting cell divisions within the germ line.
How does insulin/IGF-1 signaling exert control over the core cell cycle machinery to inhibit G2/M progression in the germ cells? Interestingly, the cell cycle arrest requires the spindle assembly checkpoint (SAC), which delays the metaphase-to-anaphase transition until the sister chromatids have completed attachments to the mitotic spindle.45 Animals that are hemizygous (i.e., Δ/+) for the SAC component encoded by mdf-1/MAD1 exhibit a germ cell hyperproliferation phenotype similar to daf-18(lf) mutant animals.40 This hyperproliferation defect is not enhanced in combination with daf-18(lf), suggesting that daf-18 and mdf-1 may act within a linear pathway.40 DAF-18 and MDF-1 appear to control the cell cycle through the activity of fzy-1, the C. elegans anaphase-promoting complex (APC) component, CDC20.40 These genetic interactions support a model wherein the DAF-18/PTEN-mediated signaling pathway promotes germline cell cycle arrest through activation of the SAC, which, in turn, inhibits APC activity to result in cell cycle arrest.40,46 A mechanism directly connecting insulin/IGF-1 signaling and the SAC is indicated by a bioinformatics analysis of AKT-1 that identified several potential phosphorylation sites on MDF-1, several of which could be phosphorylated by AKT-1 in vitro.40 Moreover, expression of a phosphorylation site-defective MDF-1 weakly suppressed the daf-18(lf) hyperproliferation phenotype, suggesting that DAF-18 may mediate germ cell arrest during nutrient stress by preventing AKT-1 phosphorylation and inhibtion of MDF-1.40 Together, these data suggest a mechanism to explain how the non-canonical insulin/IGF-1 signaling pathway can mediate a daf-16-independent G2/M arrest through control of the SAC.
Insulin/IGF-1 signaling also plays an important role in the maintenance of germline proliferation under normal, non-starvation growth conditions. Animals carrying a temperature sensitive (ts) daf-2 allele that are grown at a semi-permissive temperature do not undergo dauer formation but display decreased germline proliferation, illustrating a constitutive role for insulin signaling in promoting germline proliferation.47 The ability to separate germline arrest from dauer formation is notable, since it suggests that the cell cycle arrest does not depend on entry into the dauer arrest state.47 The arrested germ cells of these daf-2(ts) mutant animals exhibited a 4N DNA content, consistent with a G2/M delay.47 The daf-2(ts) hypoproliferation defect also requires the activity of both daf-18/PTEN and daf-16/FOXO, indicating vital functions of the downstream targets of DAF-2 activation.47 Based on RNAi analyses of putative insulin ligands, ins-3 and ins-33 may encode the insulin ligands that function to control germline proliferation.47 A genetic screen for mutations that suppress germline tumor formation also found a vital role for daf-2 in germline proliferation. This model uses a gain-of-function allele of glp-1, one of two C. elegans Notch receptor homologs, to promote the production of a germline tumor.48 The screen identified a daf-2(lf) mutation that suppresses germline tumor formation through daf-16/FOXO-dependent decrease of proliferation and increase in apoptosis.49 Putative DAF-16/FOXO target genes that mediate the arrest were subsequently identified and included both positive and negative regulators of germline tumor formation.50 Further analyses of these DAF-16 target genes may reveal the mechanism used by insulin/IGF-1 signaling to control germline proliferation.
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