Sci. STKE, 13 December 2005
CELL CYCLE Stopping Reproduction During Periods of Energy Deprivation
Mandal et al. used a mitotic recombination screen to identify a mutation that gave rise to a Drosophila eye phenotype associated with loss of cells derived from those that divide during the second mitotic wave of third instar eye disc development. Analysis of BrdU incorporation revealed that mutant cells proliferated normally during the first rounds of cell division but eventually arrested in G1. The mutation, which they named tenured, mapped to a deletion in the gene encoding the cytochrome c oxidase subunit Va (CoVa,) resulting in a null allele; somatic mutants of other mitochondrial genes yielded a similar phenotype. Block of cell cycle progression appeared to be specific: tenured mutant cells differentiated, underwent appropriate morphological changes, and did not show enhanced apoptosis. Cyclin E abundance (but not expression of the cyclin E transcript) was reduced in tenured mutant cells, whereas that of cyclins A and B was normal. When Drosophila S2 cells were treated with CoVa dsRNA, cellular ATP slowly decreased to about 43% of that in wild-type cells, and attenuation of cell proliferation paralleled this decrease. The loss of ATP was accompanied by an increase in adenosine monophosphate (AMP)-activated protein kinase (AMPK) activation (phosphorylation), and mutational analysis in vivo indicated that AMPK acted downstream of tenured. Further analysis of S2 cells treated with dsRNA and of double mutants in vivo indicated that p53 acted downstream of AMPK to regulate cyclin E abundance and G1 to S progression. Thus, the authors conclude that ATP production by the mitochondria regulates cell cycle progression through a specific signaling pathway.
S. Mandal, P. Guptan, E. Owusu-Ansah, U. Banerjee, Mitochondrial regulation of cell cycle progression during development as revealed by the tenured mutation in Drosophila. Dev. Cell 9, 843-854 (2005). [PubMed]
Citation: Stopping Reproduction During Periods of Energy Deprivation. Sci. STKE 2005, tw441 (2005).
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