Editors' ChoiceApoptosis

Protection from Afar

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Sci. Signal.  08 Jun 2010:
Vol. 3, Issue 125, pp. ec168
DOI: 10.1126/scisignal.3125ec168

A key cellular response to low oxygen concentrations involves release of the transcription factor HIF-1 (hypoxia-inducible factor 1) from prolyl hydroxylation by EGL and subsequent proteasomal degradation by the VHL ubiquitin ligase complex. This response is conserved from the nematode Caenorhabditis elegans to mammals. Sendoel et al. (see also Powell-Coffman and Coffman) found that C. elegans with a null mutation in VHL [vhl-1(ok161)] had fewer apoptotic germ cells when exposed to ionizing radiation (IR) compared with wild-type animals. IR-induced DNA damage triggers the phosphorylation and activation of the p53 homolog CED-1. In animals with a null mutation in HIF-1 [hif-1(ia4)], total abundance and phosphorylation of CED-1 was increased with IR treatment compared with wild-type animals. In contrast, the electrophoretic mobility of CED-1 in IR-treated vhl-1(ok161) animals was different, which the authors proposed may represent a posttranslational modification other than phosphorylation. The ability of HIF-1 to protect germ cells from IR-induced apoptosis required HIF-1–mediated transcription of the tyrosinase-encoding gene tyr-2. Deletion of tyr-2 [tyr-2(ok1363)] in the vhl-1(ok161) background increased IR-induced apoptosis of germ cells to almost the same extent as seen in wild-type animals. Transcriptional green fluorescent protein (GFP) reporter lines indicated that tyr-2 was expressed in the two ASJ sensory neurons in the head. IR-induced germ cell apoptosis was increased in vhl-1(ok161) animals with laser-ablated ASJ neurons, whereas it was decreased in tyr-2(ok1363) animals that overexpressed TYR-2 in ASJ neurons. Small hairpin RNA (shRNA) directed against rme-2, which encodes a cell surface protein required for endocytosis in the gonad, restored the sensitivity of germ cells in vhl-1(ok161) animals to IR, suggesting that TYR-2 secreted by ASJ neurons is endocytosed by germ cells. Human tyrosinase-related protein 2 (TRP2) is homologous to TYR-2, and knockdown of TRP2 in melanoma cells increased p53 abundance and showed increased apoptosis after treatment with the DNA chelating agent cisplatin, effects that required the catalytic activity of TRP2. Thus, HIF-1–mediated transcription of tyr-2 leads to protection of germ cells from DNA damage–induced apoptosis through effects of secreted TYR-2 on p53.

A. Sendoel, I. Kohler, C. Fellmann, S. W. Lowe, M. O. Hengartner, HIF-1 antagonizes p53-mediated apoptosis through a secreted neuronal tyrosinase. Nature 465, 577–583 (2010). [PubMed]

J. A. Powell-Coffman, C. R. Coffman, Lack of oxygen aids cell survival. Nature 465, 554–555 (2010). [PubMed]

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