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Pelle Modulates dFoxO-Mediated Cell Death in Drosophila.

Wu C, Chen Y, Wang F, Chen C, Zhang S, Li C, Li W, Wu S, Xue L - PLoS Genet. (2015)

Bottom Line: Interleukin-1 receptor-associated kinases (IRAKs) are crucial mediators of the IL-1R/TLR signaling pathways that regulate the immune and inflammation response in mammals.Finally, Pll physically interacts with dFoxO and phosphorylates dFoxO directly.This study not only identifies a previously unknown physiological function of pll in cell death, but also shed light on the mechanism of IRAKs in cell survival/death during tumorigenesis.

View Article: PubMed Central - PubMed

Affiliation: Department of Interventional Radiology, Shanghai 10th People's Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Science and Technology, Tongji University, Shanghai, China.

ABSTRACT
Interleukin-1 receptor-associated kinases (IRAKs) are crucial mediators of the IL-1R/TLR signaling pathways that regulate the immune and inflammation response in mammals. Recent studies also suggest a critical role of IRAKs in tumor development, though the underlying mechanism remains elusive. Pelle is the sole Drosophila IRAK homolog implicated in the conserved Toll pathway that regulates Dorsal/Ventral patterning, innate immune response, muscle development and axon guidance. Here we report a novel function of pll in modulating apoptotic cell death, which is independent of the Toll pathway. We found that loss of pll results in reduced size in wing tissue, which is caused by a reduction in cell number but not cell size. Depletion of pll up-regulates the transcription of pro-apoptotic genes, and triggers caspase activation and cell death. The transcription factor dFoxO is required for loss-of-pll induced cell death. Furthermore, loss of pll activates dFoxO, promotes its translocation from cytoplasm to nucleus, and up-regulates the transcription of its target gene Thor/4E-BP. Finally, Pll physically interacts with dFoxO and phosphorylates dFoxO directly. This study not only identifies a previously unknown physiological function of pll in cell death, but also shed light on the mechanism of IRAKs in cell survival/death during tumorigenesis.

No MeSH data available.


Related in: MedlinePlus

Loss of pll elicits apoptotic cell death.(A-H) AO staining of third instar larval wing discs. Compared with controls (A and E), knock down pll along the A/P boundary by ptc-gal4 (B) or in the wing pouch by Sd-Gal4 (F) triggered cell death in the corresponding areas, which was suppressed by expressing Pll (D and H), but not GFP (C and G). (I-P) X-Gal staining of a hid-LacZ and an rpr-LacZ reporters in wing discs. Compared with controls (I and M), knock down pll in the wing pouch induced hid (J) and rpr (N) transcription, which was blocked by expressing Pll (L and P), but not GFP (K and O). (Q-X) TUNEL staining of third instar larval wing discs. Compared with Gal4 controls (Q and U), knock down pll by Sd-Gal4 (R) or Omb-Gal4 (V) induced cell death in the corresponding areas, which was impeded by expressing Pll (T and X), but not GFP (S and W). In all figures, anterior is to the left and dorsal up. Detailed genotypes: (A) ptc-Gal4/+ (B) ptc-Gal4/UAS-pll-IRV2889 (C) ptc-Gal4/UAS-pll-IRV2889; UAS-GFP/+ (D) ptc-Gal4/UAS-pll-IRV2889; UAS-Pll/+ (E and Q) Sd-Gal4/+ (F and R) Sd-Gal4/+; UAS-pll-IRV2889/+ (G and S) Sd-Gal4/+; UAS-pll-IRV2889/+; UAS-GFP/+ (H and T) Sd-Gal4/+; UAS-pll-IRV2889/+; UAS-Pll/+ (I) Sd-Gal4/+; hid-LacZ/+ (J) Sd-Gal4/+; UAS-pll-IRV2889/+; hid-LacZ/+ (K) Sd-Gal4/+; UAS-pll-IRV2889/+; hid-LacZ/UAS-GFP (L) Sd-Gal4/+; UAS-pll-IRV2889/+; hid-LacZ/UAS-Pll (M) Sd-Gal4/+; rpr-LacZ/+ (N) Sd-Gal4/+; UAS-pll-IRV2889/+; rpr-LacZ/+ (O) Sd-Gal4/+; UAS-pll-IRV2889/+; rpr-LacZ/UAS-GFP (P) Sd-Gal4/+; UAS-pll-IRV2889/+; rpr-LacZ/UAS-Pll (U) Omb-Gal4/+ (V) Omb-Gal4/+; UAS-pll-IRV2889/+ (W) Omb-Gal4/+; UAS-pll-IRV2889/+; UAS-GFP/+ (X) Omb-Gal4/+; UAS-pll-IRV2889/+; UAS-Pll/+.
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pgen.1005589.g004: Loss of pll elicits apoptotic cell death.(A-H) AO staining of third instar larval wing discs. Compared with controls (A and E), knock down pll along the A/P boundary by ptc-gal4 (B) or in the wing pouch by Sd-Gal4 (F) triggered cell death in the corresponding areas, which was suppressed by expressing Pll (D and H), but not GFP (C and G). (I-P) X-Gal staining of a hid-LacZ and an rpr-LacZ reporters in wing discs. Compared with controls (I and M), knock down pll in the wing pouch induced hid (J) and rpr (N) transcription, which was blocked by expressing Pll (L and P), but not GFP (K and O). (Q-X) TUNEL staining of third instar larval wing discs. Compared with Gal4 controls (Q and U), knock down pll by Sd-Gal4 (R) or Omb-Gal4 (V) induced cell death in the corresponding areas, which was impeded by expressing Pll (T and X), but not GFP (S and W). In all figures, anterior is to the left and dorsal up. Detailed genotypes: (A) ptc-Gal4/+ (B) ptc-Gal4/UAS-pll-IRV2889 (C) ptc-Gal4/UAS-pll-IRV2889; UAS-GFP/+ (D) ptc-Gal4/UAS-pll-IRV2889; UAS-Pll/+ (E and Q) Sd-Gal4/+ (F and R) Sd-Gal4/+; UAS-pll-IRV2889/+ (G and S) Sd-Gal4/+; UAS-pll-IRV2889/+; UAS-GFP/+ (H and T) Sd-Gal4/+; UAS-pll-IRV2889/+; UAS-Pll/+ (I) Sd-Gal4/+; hid-LacZ/+ (J) Sd-Gal4/+; UAS-pll-IRV2889/+; hid-LacZ/+ (K) Sd-Gal4/+; UAS-pll-IRV2889/+; hid-LacZ/UAS-GFP (L) Sd-Gal4/+; UAS-pll-IRV2889/+; hid-LacZ/UAS-Pll (M) Sd-Gal4/+; rpr-LacZ/+ (N) Sd-Gal4/+; UAS-pll-IRV2889/+; rpr-LacZ/+ (O) Sd-Gal4/+; UAS-pll-IRV2889/+; rpr-LacZ/UAS-GFP (P) Sd-Gal4/+; UAS-pll-IRV2889/+; rpr-LacZ/UAS-Pll (U) Omb-Gal4/+ (V) Omb-Gal4/+; UAS-pll-IRV2889/+ (W) Omb-Gal4/+; UAS-pll-IRV2889/+; UAS-GFP/+ (X) Omb-Gal4/+; UAS-pll-IRV2889/+; UAS-Pll/+.

Mentions: Apoptosis plays a crucial role in maintaining tissue homeostasis, making the decision between cell death and survival in response to various intracellular and extracellular stress [36,40]. To examine the role of pll in regulating cell death, we performed acridine orange (AO) staining and TdT-mediated dUTP nick end labelling (TUNEL) assay, both are commonly used to detect apoptosis [41,42]. We found that knock-down pll in the wing disc resulted in increased AO (Fig 4A, 4B, 4E and 4F; Fig 5A and 5B; S4A, S4B, S4K and S4L Fig) and TUNEL staining (Fig 4Q, 4R, 4U and 4V; S4G–S4J Fig) in the corresponding regions, which were soundly suppressed by the expression of Pll (Fig 4D, 4H, 4T and 4X), but not that of GFP (Fig 4C, 4G, 4S and 4W), indicating pll negatively regulates cell death in wing development.


Pelle Modulates dFoxO-Mediated Cell Death in Drosophila.

Wu C, Chen Y, Wang F, Chen C, Zhang S, Li C, Li W, Wu S, Xue L - PLoS Genet. (2015)

Loss of pll elicits apoptotic cell death.(A-H) AO staining of third instar larval wing discs. Compared with controls (A and E), knock down pll along the A/P boundary by ptc-gal4 (B) or in the wing pouch by Sd-Gal4 (F) triggered cell death in the corresponding areas, which was suppressed by expressing Pll (D and H), but not GFP (C and G). (I-P) X-Gal staining of a hid-LacZ and an rpr-LacZ reporters in wing discs. Compared with controls (I and M), knock down pll in the wing pouch induced hid (J) and rpr (N) transcription, which was blocked by expressing Pll (L and P), but not GFP (K and O). (Q-X) TUNEL staining of third instar larval wing discs. Compared with Gal4 controls (Q and U), knock down pll by Sd-Gal4 (R) or Omb-Gal4 (V) induced cell death in the corresponding areas, which was impeded by expressing Pll (T and X), but not GFP (S and W). In all figures, anterior is to the left and dorsal up. Detailed genotypes: (A) ptc-Gal4/+ (B) ptc-Gal4/UAS-pll-IRV2889 (C) ptc-Gal4/UAS-pll-IRV2889; UAS-GFP/+ (D) ptc-Gal4/UAS-pll-IRV2889; UAS-Pll/+ (E and Q) Sd-Gal4/+ (F and R) Sd-Gal4/+; UAS-pll-IRV2889/+ (G and S) Sd-Gal4/+; UAS-pll-IRV2889/+; UAS-GFP/+ (H and T) Sd-Gal4/+; UAS-pll-IRV2889/+; UAS-Pll/+ (I) Sd-Gal4/+; hid-LacZ/+ (J) Sd-Gal4/+; UAS-pll-IRV2889/+; hid-LacZ/+ (K) Sd-Gal4/+; UAS-pll-IRV2889/+; hid-LacZ/UAS-GFP (L) Sd-Gal4/+; UAS-pll-IRV2889/+; hid-LacZ/UAS-Pll (M) Sd-Gal4/+; rpr-LacZ/+ (N) Sd-Gal4/+; UAS-pll-IRV2889/+; rpr-LacZ/+ (O) Sd-Gal4/+; UAS-pll-IRV2889/+; rpr-LacZ/UAS-GFP (P) Sd-Gal4/+; UAS-pll-IRV2889/+; rpr-LacZ/UAS-Pll (U) Omb-Gal4/+ (V) Omb-Gal4/+; UAS-pll-IRV2889/+ (W) Omb-Gal4/+; UAS-pll-IRV2889/+; UAS-GFP/+ (X) Omb-Gal4/+; UAS-pll-IRV2889/+; UAS-Pll/+.
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Related In: Results  -  Collection

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Show All Figures
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pgen.1005589.g004: Loss of pll elicits apoptotic cell death.(A-H) AO staining of third instar larval wing discs. Compared with controls (A and E), knock down pll along the A/P boundary by ptc-gal4 (B) or in the wing pouch by Sd-Gal4 (F) triggered cell death in the corresponding areas, which was suppressed by expressing Pll (D and H), but not GFP (C and G). (I-P) X-Gal staining of a hid-LacZ and an rpr-LacZ reporters in wing discs. Compared with controls (I and M), knock down pll in the wing pouch induced hid (J) and rpr (N) transcription, which was blocked by expressing Pll (L and P), but not GFP (K and O). (Q-X) TUNEL staining of third instar larval wing discs. Compared with Gal4 controls (Q and U), knock down pll by Sd-Gal4 (R) or Omb-Gal4 (V) induced cell death in the corresponding areas, which was impeded by expressing Pll (T and X), but not GFP (S and W). In all figures, anterior is to the left and dorsal up. Detailed genotypes: (A) ptc-Gal4/+ (B) ptc-Gal4/UAS-pll-IRV2889 (C) ptc-Gal4/UAS-pll-IRV2889; UAS-GFP/+ (D) ptc-Gal4/UAS-pll-IRV2889; UAS-Pll/+ (E and Q) Sd-Gal4/+ (F and R) Sd-Gal4/+; UAS-pll-IRV2889/+ (G and S) Sd-Gal4/+; UAS-pll-IRV2889/+; UAS-GFP/+ (H and T) Sd-Gal4/+; UAS-pll-IRV2889/+; UAS-Pll/+ (I) Sd-Gal4/+; hid-LacZ/+ (J) Sd-Gal4/+; UAS-pll-IRV2889/+; hid-LacZ/+ (K) Sd-Gal4/+; UAS-pll-IRV2889/+; hid-LacZ/UAS-GFP (L) Sd-Gal4/+; UAS-pll-IRV2889/+; hid-LacZ/UAS-Pll (M) Sd-Gal4/+; rpr-LacZ/+ (N) Sd-Gal4/+; UAS-pll-IRV2889/+; rpr-LacZ/+ (O) Sd-Gal4/+; UAS-pll-IRV2889/+; rpr-LacZ/UAS-GFP (P) Sd-Gal4/+; UAS-pll-IRV2889/+; rpr-LacZ/UAS-Pll (U) Omb-Gal4/+ (V) Omb-Gal4/+; UAS-pll-IRV2889/+ (W) Omb-Gal4/+; UAS-pll-IRV2889/+; UAS-GFP/+ (X) Omb-Gal4/+; UAS-pll-IRV2889/+; UAS-Pll/+.
Mentions: Apoptosis plays a crucial role in maintaining tissue homeostasis, making the decision between cell death and survival in response to various intracellular and extracellular stress [36,40]. To examine the role of pll in regulating cell death, we performed acridine orange (AO) staining and TdT-mediated dUTP nick end labelling (TUNEL) assay, both are commonly used to detect apoptosis [41,42]. We found that knock-down pll in the wing disc resulted in increased AO (Fig 4A, 4B, 4E and 4F; Fig 5A and 5B; S4A, S4B, S4K and S4L Fig) and TUNEL staining (Fig 4Q, 4R, 4U and 4V; S4G–S4J Fig) in the corresponding regions, which were soundly suppressed by the expression of Pll (Fig 4D, 4H, 4T and 4X), but not that of GFP (Fig 4C, 4G, 4S and 4W), indicating pll negatively regulates cell death in wing development.

Bottom Line: Interleukin-1 receptor-associated kinases (IRAKs) are crucial mediators of the IL-1R/TLR signaling pathways that regulate the immune and inflammation response in mammals.Finally, Pll physically interacts with dFoxO and phosphorylates dFoxO directly.This study not only identifies a previously unknown physiological function of pll in cell death, but also shed light on the mechanism of IRAKs in cell survival/death during tumorigenesis.

View Article: PubMed Central - PubMed

Affiliation: Department of Interventional Radiology, Shanghai 10th People's Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Science and Technology, Tongji University, Shanghai, China.

ABSTRACT
Interleukin-1 receptor-associated kinases (IRAKs) are crucial mediators of the IL-1R/TLR signaling pathways that regulate the immune and inflammation response in mammals. Recent studies also suggest a critical role of IRAKs in tumor development, though the underlying mechanism remains elusive. Pelle is the sole Drosophila IRAK homolog implicated in the conserved Toll pathway that regulates Dorsal/Ventral patterning, innate immune response, muscle development and axon guidance. Here we report a novel function of pll in modulating apoptotic cell death, which is independent of the Toll pathway. We found that loss of pll results in reduced size in wing tissue, which is caused by a reduction in cell number but not cell size. Depletion of pll up-regulates the transcription of pro-apoptotic genes, and triggers caspase activation and cell death. The transcription factor dFoxO is required for loss-of-pll induced cell death. Furthermore, loss of pll activates dFoxO, promotes its translocation from cytoplasm to nucleus, and up-regulates the transcription of its target gene Thor/4E-BP. Finally, Pll physically interacts with dFoxO and phosphorylates dFoxO directly. This study not only identifies a previously unknown physiological function of pll in cell death, but also shed light on the mechanism of IRAKs in cell survival/death during tumorigenesis.

No MeSH data available.


Related in: MedlinePlus