Dpp signaling and the induction of neoplastic tumors by caspase-inhibited apoptotic cells in Drosophila.
In Drosophila, stresses such as x-irradiation or severe heat shock can cause most epidermal cells to die by apoptosis. Yet, the remaining cells recover from such assaults and form normal adult structures, indicating that they undergo extra growth to replace the lost cells. Recent studies of cells in which the cell death pathway is blocked by expression of the caspase inhibitor P35 have raised the possibility that dying cells normally regulate this compensatory growth by serving as transient sources of mitogenic signals. Caspase-inhibited cells that initiate apoptosis do not die. Instead, they persist in an "undead" state in which they ectopically express the signaling genes decapentaplegic (dpp) and wingless (wg) and induce abnormal growth and proliferation of surrounding tissue. Here, using mutations to abolish Dpp and/or Wg signaling by such undead cells, we show that Dpp and Wg constitute opposing stimulatory and inhibitory signals that regulate this excess growth and proliferation. Strikingly, we also found that, when Wg signaling is blocked, unfettered Dpp signaling by undead cells transforms their neighbors into neoplastic tumors, provided that caspase activity is also blocked in the responding cells. This phenomenon may provide a paradigm for the formation of neoplastic tumors in mammalian tissues that are defective in executing the cell death pathway. Specifically, we suggest that stress events (exposure to chemical mutagens, viral infection, or irradiation) that initiate apoptosis in such tissues generate undead cells, and that imbalances in growth regulatory signals sent by these cells can induce the oncogenic transformation of neighboring cells.
Pérez-Garijo
Ainhoa
A
Centro de Biología Molecular, Universidad Autónoma de Madrid, 28049 Madrid, Spain.
Martín
Francisco A
FA
Struhl
Gary
G
Morata
Ginés
G
D000818:Animals; D017209:Apoptosis / Q000528:radiation effects; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism*; D002471:Cell Transformation, Neoplastic; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004198:Disease Susceptibility; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000166:cytology* / Q000235:genetics / Q000254:growth & development / Q000378:metabolism*; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics; D051155:Wnt1 Protein; D014965:X-Rays
D061945:Caspase Inhibitors; D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; C102284:Myc protein, Drosophila; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; D051155:Wnt1 Protein; C064196:dpp protein, Drosophila; C074622:wg protein, Drosophila; D020169:Caspases