Cell-Nonautonomous Regulation of C. elegans Germ Cell Death by kri-1

TY - JOUR

T1 - Cell-Nonautonomous Regulation of C. elegans Germ Cell Death by kri-1

AU - Ito, Shu

AU - Greiss, Sebastian

AU - Gartner, Anton

AU - Derry, W. Brent

PY - 2010/2/23

Y1 - 2010/2/23

N2 - Programmed cell death (or apoptosis) is an evolutionarily conserved, genetically controlled suicide mechanism for cells that, when deregulated, can lead to developmental defects, cancers, and degenerative diseases [1, 2]. In C. elegans, DNA damage induces germ cell death by signaling through cep-1/p53, ultimately leading to the activation of CED-3/caspase [3-13]. It has been hypothesized that the major regulatory events controlling cell death occur by cell-autonomous mechanisms, that is, within the dying cell. In support of this, genetic studies in C. elegans have shown that the core apoptosis pathway genes ced-4l APAF-1 and ced-3/caspase are required in cells fated to die [9]. However, it is not known whether the upstream signals that activate apoptosis function in a cell-autonomous manner. Here we show that kri-1, an ortholog of KRIT1/CCM1, which is mutated in the human neurovascular disease cerebral cavernous malformation [14, 15], is required to activate DNA damage-dependent cell death independently of cep-1/p53. Interestingly, we find that kri-1 regulates cell death in a cell-nonautonomous manner, revealing a novel regulatory role for nondying cells in eliciting cell death in response to DNA damage.

AB - Programmed cell death (or apoptosis) is an evolutionarily conserved, genetically controlled suicide mechanism for cells that, when deregulated, can lead to developmental defects, cancers, and degenerative diseases [1, 2]. In C. elegans, DNA damage induces germ cell death by signaling through cep-1/p53, ultimately leading to the activation of CED-3/caspase [3-13]. It has been hypothesized that the major regulatory events controlling cell death occur by cell-autonomous mechanisms, that is, within the dying cell. In support of this, genetic studies in C. elegans have shown that the core apoptosis pathway genes ced-4l APAF-1 and ced-3/caspase are required in cells fated to die [9]. However, it is not known whether the upstream signals that activate apoptosis function in a cell-autonomous manner. Here we show that kri-1, an ortholog of KRIT1/CCM1, which is mutated in the human neurovascular disease cerebral cavernous malformation [14, 15], is required to activate DNA damage-dependent cell death independently of cep-1/p53. Interestingly, we find that kri-1 regulates cell death in a cell-nonautonomous manner, revealing a novel regulatory role for nondying cells in eliciting cell death in response to DNA damage.

KW - DAMAGE-INDUCED APOPTOSIS

KW - DNA-DAMAGE

KW - CAENORHABDITIS-ELEGANS

KW - CHECKPOINT PROTEIN

KW - LIFE-SPAN

KW - TUMOR-SUPPRESSOR

KW - ENCODING KRIT1

KW - GENE

KW - CED-4

KW - P53

U2 - 10.1016/j.cub.2009.12.032

DO - 10.1016/j.cub.2009.12.032

M3 - Article

C2 - 20137949

SN - 0960-9822

VL - 20

SP - 333

EP - 338

JO - Current Biology

JF - Current Biology

IS - 4

ER -