Regulation of the cell cycle can be directly linked to many genes involved in human cancer, as there is an intimate link between oncogenes and the machinery involved in controlling cell proliferation. The tumor suppressor gene
p53 , is among the most frequently mutated genes in human cancer.
p53 plays a vital role in coordinating cellular responses to DNA damage and genotoxic stress via activation of DNA repair machinery, promotion of apoptosis, or transient arrest of the cell cycle. In the model organism C. elegans , there is only one
p53 family member, CEP-1, which has functional roles in both the germ-line and soma (1). Previous microarray experiments have shown that the gene
phg-1 , a member of the pharynx-associated gas related gene class, is upregulated 3-fold in response to UV radiation in a
cep-1 dependent manner (2).
phg-1 is a homologue of the human growth arrest specific gene,
gas-1 .
gas-1 , which encodes a GPI anchor protein associated with the plasma membrane, is expressed during the G 0 phase of the cell cycle, and when overexpressed in proliferating murine fibroblasts, it induces growth arrest (3). Although this growth arrest has been shown to be
p53-dependent, the mechanism by which
p53 and GAS-1 interact remains unknown. A putative
p53 consensus binding site was found in the first intron of
phg-1 , supporting a role for
phg-1 as a direct transcriptional target of CEP-1 (2). Ablation induced by RNA interference has shown that PHG-1 is required to arrest proliferation of mitotic germ cells in response to UV radiation (2). However, unlike CEP-1, PHG-1 is not involved in apoptosis of the meiotic germ-line, implying that PHG-1 is downstream of CEP-1 (2). DNA damage-induced signaling activates checkpoint pathways in cells, which leads to cell cycle arrest or apoptosis. This mechanism fails to occur in
rad-5(
mn159) and
clk-2(
qm37) worms, which are allelic (4). These mutants are defective for the S phase replication checkpoint (4), suggesting that RAD-5/CLK-2 and PHG-1 may be functioning in the same pathway. Using RNAi directed against
phg-1 , we have recently shown that the slow growth rate phenotype exhibited by
clk-2(
qm37) mutant worms can be rescued. We have observed similar results when
rad-5(
mn159) worms were fed
phg-1 RNAi, but with a less pronounced phenotype as
clk-2(
qm37) is a stronger allele (4). Restoration of normal growth rate is also seen in these two mutant worm strains when they are fed
cep-1 RNAi. A possible explanation for this is that when
rad-5/clk-2 is knocked out, a stress signal is communicated to
cep-1 , inducing its activity and upregulating
phg-1 . Thus, we hypothesize that PHG-1 is a downstream effector of the DNA damage checkpoint protein RAD-5/CLK-2, and consistent with a function of PHG-1 in the C. elegans mitotic germ-line, we also believe that it plays a role in regulating developmental rate in the soma. References (1) Derry et al., (2001), Science, 294: 591-595. (2) Derry et al., (2003), International C. elegans Meeting: 240 (3) Agostoni et al., (2002), Biochimica et Biophysica Acta, 1574: 1-9. (4) Ahmed et al., (2001), Current Biology, 11: 1934-1944.