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News April 14, 2021 //--- p53 mutation (mtp53) is a well-known cancer-promoting gene.
In a recent study, the team of Luis A.
Martinez from Stony Brook University reported a new mechanism through which mtp53 inhibits cell-autonomous and non-cell-autonomous signals, thereby promoting cancer cell survival and evading tumor immune surveillance.
Related results were published in the recent "Cancer Cell" magazine.
In a recent study, the team of Luis A.
Martinez from Stony Brook University reported a new mechanism through which mtp53 inhibits cell-autonomous and non-cell-autonomous signals, thereby promoting cancer cell survival and evading tumor immune surveillance.
Related results were published in the recent "Cancer Cell" magazine.
(Image source: www.
cell.
com)
cell.
com)
In order to determine whether mtp53 regulates innate immune signaling pathways, the authors initially studied human breast cancer cells BT549 (p53R249S) and MDA-MB-231 (p53R280K) and pancreatic cell lines MIA PaCa-2 (p53R248W) (human origin) and KPC (p53R172H).
) (Mouse source) ShRNA-mediated mtp53 knockdown was performed.
In all four cell lines, the authors observed that mtp53 knockdown caused phosphorylation of TBK1 and its substrates IRF3 and STING.
Although the mouse and human p53 targeting sequences are different, they both produce similar responses.
In addition, the authors tried two other different p53 shRNAs, and also found that they can also induce phosphorylation of TBK1 substrates in MDA-MB-231 cells, thereby eliminating shRNA off-target effects.
In addition, by comparing mouse embryonic fibroblasts (MEF) derived from p53-/- or mtp53 (p53R172H/R172H) mouse models, the authors found that mtp53 is associated with decreased phosphorylation of TBK1, IRF3 and STING.
On this basis, the authors constructed a 4T1 mouse breast cancer cell line (which lacks the p53 gene) to express the R249S mutant mtp53, and found that the phosphorylation level of TBK1 substrate in these cells was reduced.
mtp53 (R280K) was overexpressed in two different types of normal human fibroblasts, and it also reduced the phosphorylation of TBK1 and its substrates IRF3 and STING.
These data indicate that mtp53 has the activity of blocking innate immune signaling pathways.
) (Mouse source) ShRNA-mediated mtp53 knockdown was performed.
In all four cell lines, the authors observed that mtp53 knockdown caused phosphorylation of TBK1 and its substrates IRF3 and STING.
Although the mouse and human p53 targeting sequences are different, they both produce similar responses.
In addition, the authors tried two other different p53 shRNAs, and also found that they can also induce phosphorylation of TBK1 substrates in MDA-MB-231 cells, thereby eliminating shRNA off-target effects.
In addition, by comparing mouse embryonic fibroblasts (MEF) derived from p53-/- or mtp53 (p53R172H/R172H) mouse models, the authors found that mtp53 is associated with decreased phosphorylation of TBK1, IRF3 and STING.
On this basis, the authors constructed a 4T1 mouse breast cancer cell line (which lacks the p53 gene) to express the R249S mutant mtp53, and found that the phosphorylation level of TBK1 substrate in these cells was reduced.
mtp53 (R280K) was overexpressed in two different types of normal human fibroblasts, and it also reduced the phosphorylation of TBK1 and its substrates IRF3 and STING.
These data indicate that mtp53 has the activity of blocking innate immune signaling pathways.
(Figure 1, p53 mutation inhibits the transmission of natural immune cells)
In contrast to mtp53, shRNA was used to knock down the expression level of wild-type p53 in human lung cancer A549 cells, resulting in decreased phosphorylation of STING, TBK1 and IRF3.
In addition, increased phosphorylation of TBK1, STING and IRF3 was observed in human lung cancer H1299 cells that induced the expression of wild-type p53.
The phosphorylation of these proteins may reflect the p53-mediated activity of IFI16, which works in concert with cGAS to activate the TBK1-STING-IRF3 signal.
However, IFI16 levels are not affected by mtp53 knockdown or overexpression in different cell lines.
Therefore, wild-type p53 and mtp53 function in opposite ways in the control of innate immune signaling pathways.
In addition, increased phosphorylation of TBK1, STING and IRF3 was observed in human lung cancer H1299 cells that induced the expression of wild-type p53.
The phosphorylation of these proteins may reflect the p53-mediated activity of IFI16, which works in concert with cGAS to activate the TBK1-STING-IRF3 signal.
However, IFI16 levels are not affected by mtp53 knockdown or overexpression in different cell lines.
Therefore, wild-type p53 and mtp53 function in opposite ways in the control of innate immune signaling pathways.
(Figure 2, p53 mutation affects the localization of IRF-3 and its mediated apoptosis)
After the innate immune pathway is activated, STING and IRF3 will relocate to different intracellular regions, so the authors investigated whether mtp53 changed its subcellular localization.
The staining of STING and ERGIC indicated that the localization of STING in the Golgi apparatus is consistent with the previously reported observations that it is active in cancer cells.
In addition, the data showed that cGAS and STING knockdown can reduce the phosphorylation of TBK1 and IRF3.
Importantly, treatment with cGAMP in BT549 and MDA-MB-231 cells can further increase the co-localization of STING and ERGIC.
The staining of STING and ERGIC indicated that the localization of STING in the Golgi apparatus is consistent with the previously reported observations that it is active in cancer cells.
In addition, the data showed that cGAS and STING knockdown can reduce the phosphorylation of TBK1 and IRF3.
Importantly, treatment with cGAMP in BT549 and MDA-MB-231 cells can further increase the co-localization of STING and ERGIC.
Next, the author checked whether mtp53 controls IRF3 translocation.
IRF3 is present in the cytoplasm in unstimulated cells, but after activating the STING/TBK1/IRF3 pathway, it transfers to the nucleus.
To evaluate whether mtp53 regulates the subcellular localization of IRF3, the authors stably expressed GFP-IRF3 in H1299 cells with doxycycline-induced mtp53R248W.
In uninduced cells, GFP-IRF3 is present in the cytoplasm.
After HT-DNA treatment, GFP-IRF3 is transferred to the nucleus in about 90% of the cells.
Conversely, mtp53 expression weakened the response of GFP-IRF3 to HT-DNA treatment, and the proportion of GFP-IRF3 in the nucleus was less than 20%.
Comprehensive data show that mtp53 can hinder the nuclear translocation of IRF3.
IRF3 is present in the cytoplasm in unstimulated cells, but after activating the STING/TBK1/IRF3 pathway, it transfers to the nucleus.
To evaluate whether mtp53 regulates the subcellular localization of IRF3, the authors stably expressed GFP-IRF3 in H1299 cells with doxycycline-induced mtp53R248W.
In uninduced cells, GFP-IRF3 is present in the cytoplasm.
After HT-DNA treatment, GFP-IRF3 is transferred to the nucleus in about 90% of the cells.
Conversely, mtp53 expression weakened the response of GFP-IRF3 to HT-DNA treatment, and the proportion of GFP-IRF3 in the nucleus was less than 20%.
Comprehensive data show that mtp53 can hinder the nuclear translocation of IRF3.
Cytoplasmic DNA signals can activate IRF3, which in turn induces the corresponding transcription process.
At the same time, DNA signals also induce IRF3-dependent cell death, that is, IRF3 interacts with BAX and promotes the formation of mitochondrial pores and apoptosis.
The authors found that about 40% of H1299 cells treated with HT-DNA for 24 hours appeared apoptosis, and the above phenomenon no longer appeared after shRNA-mediated IRF3 knockout, indicating that the cell's apoptosis response to HT-DNA-induced apoptosis was IRF3 Dependent.
To investigate whether mtp53 can inhibit this apoptotic response, the authors knocked down mtp53 in MDA-MB-231 cells and treated them with HT-DNA.
The results show that HT-DNA treatment can induce apoptosis of about 30% of control cells, and the apoptotic response of mtp53 knockdown cells is more obvious.
In addition, the combination of mtp53 knockout and IRF3 knockout can reduce the apoptotic response to 20%.
Overall, these data indicate that cells expressing mtp53 failed to elicit the cellular innate immune response to cGAS/STING/TBK1/IRF3 pathway activation.
Finally, the authors found that mtp53 can inhibit the formation of the TBK1-STING-IRF3 complex, thus revealing the reason for its negative regulation of innate immune signals from the molecular mechanism level.
At the same time, DNA signals also induce IRF3-dependent cell death, that is, IRF3 interacts with BAX and promotes the formation of mitochondrial pores and apoptosis.
The authors found that about 40% of H1299 cells treated with HT-DNA for 24 hours appeared apoptosis, and the above phenomenon no longer appeared after shRNA-mediated IRF3 knockout, indicating that the cell's apoptosis response to HT-DNA-induced apoptosis was IRF3 Dependent.
To investigate whether mtp53 can inhibit this apoptotic response, the authors knocked down mtp53 in MDA-MB-231 cells and treated them with HT-DNA.
The results show that HT-DNA treatment can induce apoptosis of about 30% of control cells, and the apoptotic response of mtp53 knockdown cells is more obvious.
In addition, the combination of mtp53 knockout and IRF3 knockout can reduce the apoptotic response to 20%.
Overall, these data indicate that cells expressing mtp53 failed to elicit the cellular innate immune response to cGAS/STING/TBK1/IRF3 pathway activation.
Finally, the authors found that mtp53 can inhibit the formation of the TBK1-STING-IRF3 complex, thus revealing the reason for its negative regulation of innate immune signals from the molecular mechanism level.
In summary, the authors found that Mtp53 interfered with cytoplasmic DNA-mediated cGAS-STING-TBK1-IRF3 signal transmission in the activation of innate immune response.
It reveals the internal reason why tumor cells resist immune surveillance, and does not provide new ideas for future tumor immunotherapy.
(Bioon.
com)
It reveals the internal reason why tumor cells resist immune surveillance, and does not provide new ideas for future tumor immunotherapy.
(Bioon.
com)
Original source: Monisankar Ghosh, Suchandrima Saha, Julie Bettke.
Mutant p53 suppresses innate immune signaling to promote tumorigenesis.
Cancer Cell (2021).
DOI: https://doi.
org/10.
1016/j.
ccell.
2021.
01.
003
Mutant p53 suppresses innate immune signaling to promote tumorigenesis.
Cancer Cell (2021).
DOI: https://doi.
org/10.
1016/j.
ccell.
2021.
01.
003
(Figure 1, p53 mutation inhibits the transmission of natural immune cells)
In contrast to mtp53, shRNA was used to knock down the expression level of wild-type p53 in human lung cancer A549 cells, resulting in decreased phosphorylation of STING, TBK1 and IRF3.
In addition, increased phosphorylation of TBK1, STING and IRF3 was observed in human lung cancer H1299 cells that induced the expression of wild-type p53.
The phosphorylation of these proteins may reflect the p53-mediated activity of IFI16, which works in concert with cGAS to activate the TBK1-STING-IRF3 signal.
However, IFI16 levels are not affected by mtp53 knockdown or overexpression in different cell lines.
Therefore, wild-type p53 and mtp53 function in opposite ways in the control of innate immune signaling pathways.
In addition, increased phosphorylation of TBK1, STING and IRF3 was observed in human lung cancer H1299 cells that induced the expression of wild-type p53.
The phosphorylation of these proteins may reflect the p53-mediated activity of IFI16, which works in concert with cGAS to activate the TBK1-STING-IRF3 signal.
However, IFI16 levels are not affected by mtp53 knockdown or overexpression in different cell lines.
Therefore, wild-type p53 and mtp53 function in opposite ways in the control of innate immune signaling pathways.
(Figure 2, p53 mutation affects the localization of IRF-3 and its mediated apoptosis)
After the innate immune pathway is activated, STING and IRF3 will relocate to different intracellular regions, so the authors investigated whether mtp53 changed its subcellular localization.
The staining of STING and ERGIC indicated that the localization of STING in the Golgi apparatus is consistent with the previously reported observations that it is active in cancer cells.
In addition, the data showed that cGAS and STING knockdown can reduce the phosphorylation of TBK1 and IRF3.
Importantly, treatment with cGAMP in BT549 and MDA-MB-231 cells can further increase the co-localization of STING and ERGIC.
The staining of STING and ERGIC indicated that the localization of STING in the Golgi apparatus is consistent with the previously reported observations that it is active in cancer cells.
In addition, the data showed that cGAS and STING knockdown can reduce the phosphorylation of TBK1 and IRF3.
Importantly, treatment with cGAMP in BT549 and MDA-MB-231 cells can further increase the co-localization of STING and ERGIC.
Next, the author checked whether mtp53 controls IRF3 translocation.
IRF3 is present in the cytoplasm in unstimulated cells, but after activating the STING/TBK1/IRF3 pathway, it transfers to the nucleus.
To evaluate whether mtp53 regulates the subcellular localization of IRF3, the authors stably expressed GFP-IRF3 in H1299 cells with doxycycline-induced mtp53R248W.
In uninduced cells, GFP-IRF3 is present in the cytoplasm.
After HT-DNA treatment, GFP-IRF3 is transferred to the nucleus in about 90% of the cells.
Conversely, mtp53 expression weakened the response of GFP-IRF3 to HT-DNA treatment, and the proportion of GFP-IRF3 in the nucleus was less than 20%.
Comprehensive data show that mtp53 can hinder the nuclear translocation of IRF3.
IRF3 is present in the cytoplasm in unstimulated cells, but after activating the STING/TBK1/IRF3 pathway, it transfers to the nucleus.
To evaluate whether mtp53 regulates the subcellular localization of IRF3, the authors stably expressed GFP-IRF3 in H1299 cells with doxycycline-induced mtp53R248W.
In uninduced cells, GFP-IRF3 is present in the cytoplasm.
After HT-DNA treatment, GFP-IRF3 is transferred to the nucleus in about 90% of the cells.
Conversely, mtp53 expression weakened the response of GFP-IRF3 to HT-DNA treatment, and the proportion of GFP-IRF3 in the nucleus was less than 20%.
Comprehensive data show that mtp53 can hinder the nuclear translocation of IRF3.
Cytoplasmic DNA signals can activate IRF3, which in turn induces the corresponding transcription process.
At the same time, DNA signals also induce IRF3-dependent cell death, that is, IRF3 interacts with BAX and promotes the formation of mitochondrial pores and apoptosis.
The authors found that about 40% of H1299 cells treated with HT-DNA for 24 hours appeared apoptosis, and the above phenomenon no longer appeared after shRNA-mediated IRF3 knockout, indicating that the cell's apoptosis response to HT-DNA-induced apoptosis was IRF3 Dependent.
To investigate whether mtp53 can inhibit this apoptotic response, the authors knocked down mtp53 in MDA-MB-231 cells and treated them with HT-DNA.
The results show that HT-DNA treatment can induce apoptosis of about 30% of control cells, and the apoptotic response of mtp53 knockdown cells is more obvious.
In addition, the combination of mtp53 knockout and IRF3 knockout can reduce the apoptotic response to 20%.
Overall, these data indicate that cells expressing mtp53 failed to elicit the cellular innate immune response to cGAS/STING/TBK1/IRF3 pathway activation.
Finally, the authors found that mtp53 can inhibit the formation of the TBK1-STING-IRF3 complex, thus revealing the reason for its negative regulation of innate immune signals from the molecular mechanism level.
At the same time, DNA signals also induce IRF3-dependent cell death, that is, IRF3 interacts with BAX and promotes the formation of mitochondrial pores and apoptosis.
The authors found that about 40% of H1299 cells treated with HT-DNA for 24 hours appeared apoptosis, and the above phenomenon no longer appeared after shRNA-mediated IRF3 knockout, indicating that the cell's apoptosis response to HT-DNA-induced apoptosis was IRF3 Dependent.
To investigate whether mtp53 can inhibit this apoptotic response, the authors knocked down mtp53 in MDA-MB-231 cells and treated them with HT-DNA.
The results show that HT-DNA treatment can induce apoptosis of about 30% of control cells, and the apoptotic response of mtp53 knockdown cells is more obvious.
In addition, the combination of mtp53 knockout and IRF3 knockout can reduce the apoptotic response to 20%.
Overall, these data indicate that cells expressing mtp53 failed to elicit the cellular innate immune response to cGAS/STING/TBK1/IRF3 pathway activation.
Finally, the authors found that mtp53 can inhibit the formation of the TBK1-STING-IRF3 complex, thus revealing the reason for its negative regulation of innate immune signals from the molecular mechanism level.
In summary, the authors found that Mtp53 interfered with cytoplasmic DNA-mediated cGAS-STING-TBK1-IRF3 signal transmission in the activation of innate immune response.
It reveals the internal reason why tumor cells resist immune surveillance, and does not provide new ideas for future tumor immunotherapy.
(Bioon.
com)
It reveals the internal reason why tumor cells resist immune surveillance, and does not provide new ideas for future tumor immunotherapy.
(Bioon.
com)
Original source: Monisankar Ghosh, Suchandrima Saha, Julie Bettke.
Mutant p53 suppresses innate immune signaling to promote tumorigenesis.
Cancer Cell (2021).
DOI: https://doi.
org/10.
1016/j.
ccell.
2021.
01.
003
Mutant p53 suppresses innate immune signaling to promote tumorigenesis.
Cancer Cell (2021).
DOI: https://doi.
org/10.
1016/j.
ccell.
2021.
01.
003
(Figure 2, p53 mutation affects the localization of IRF-3 and its mediated apoptosis)
After the innate immune pathway is activated, STING and IRF3 will relocate to different intracellular regions, so the authors investigated whether mtp53 changed its subcellular localization.
The staining of STING and ERGIC indicated that the localization of STING in the Golgi apparatus is consistent with the previously reported observations that it is active in cancer cells.
In addition, the data showed that cGAS and STING knockdown can reduce the phosphorylation of TBK1 and IRF3.
Importantly, treatment with cGAMP in BT549 and MDA-MB-231 cells can further increase the co-localization of STING and ERGIC.
The staining of STING and ERGIC indicated that the localization of STING in the Golgi apparatus is consistent with the previously reported observations that it is active in cancer cells.
In addition, the data showed that cGAS and STING knockdown can reduce the phosphorylation of TBK1 and IRF3.
Importantly, treatment with cGAMP in BT549 and MDA-MB-231 cells can further increase the co-localization of STING and ERGIC.
Next, the author checked whether mtp53 controls IRF3 translocation.
IRF3 is present in the cytoplasm in unstimulated cells, but after activating the STING/TBK1/IRF3 pathway, it transfers to the nucleus.
To evaluate whether mtp53 regulates the subcellular localization of IRF3, the authors stably expressed GFP-IRF3 in H1299 cells with doxycycline-induced mtp53R248W.
In uninduced cells, GFP-IRF3 is present in the cytoplasm.
After HT-DNA treatment, GFP-IRF3 is transferred to the nucleus in about 90% of the cells.
Conversely, mtp53 expression weakened the response of GFP-IRF3 to HT-DNA treatment, and the proportion of GFP-IRF3 in the nucleus was less than 20%.
Comprehensive data show that mtp53 can hinder the nuclear translocation of IRF3.
IRF3 is present in the cytoplasm in unstimulated cells, but after activating the STING/TBK1/IRF3 pathway, it transfers to the nucleus.
To evaluate whether mtp53 regulates the subcellular localization of IRF3, the authors stably expressed GFP-IRF3 in H1299 cells with doxycycline-induced mtp53R248W.
In uninduced cells, GFP-IRF3 is present in the cytoplasm.
After HT-DNA treatment, GFP-IRF3 is transferred to the nucleus in about 90% of the cells.
Conversely, mtp53 expression weakened the response of GFP-IRF3 to HT-DNA treatment, and the proportion of GFP-IRF3 in the nucleus was less than 20%.
Comprehensive data show that mtp53 can hinder the nuclear translocation of IRF3.
Cytoplasmic DNA signals can activate IRF3, which in turn induces the corresponding transcription process.
At the same time, DNA signals also induce IRF3-dependent cell death, that is, IRF3 interacts with BAX and promotes the formation of mitochondrial pores and apoptosis.
The authors found that about 40% of H1299 cells treated with HT-DNA for 24 hours appeared apoptosis, and the above phenomenon no longer appeared after shRNA-mediated IRF3 knockout, indicating that the cell's apoptosis response to HT-DNA-induced apoptosis was IRF3 Dependent.
To investigate whether mtp53 can inhibit this apoptotic response, the authors knocked down mtp53 in MDA-MB-231 cells and treated them with HT-DNA.
The results show that HT-DNA treatment can induce apoptosis of about 30% of control cells, and the apoptotic response of mtp53 knockdown cells is more obvious.
In addition, the combination of mtp53 knockout and IRF3 knockout can reduce the apoptotic response to 20%.
Overall, these data indicate that cells expressing mtp53 failed to elicit the cellular innate immune response to cGAS/STING/TBK1/IRF3 pathway activation.
Finally, the authors found that mtp53 can inhibit the formation of the TBK1-STING-IRF3 complex, thus revealing the reason for its negative regulation of innate immune signals from the molecular mechanism level.
At the same time, DNA signals also induce IRF3-dependent cell death, that is, IRF3 interacts with BAX and promotes the formation of mitochondrial pores and apoptosis.
The authors found that about 40% of H1299 cells treated with HT-DNA for 24 hours appeared apoptosis, and the above phenomenon no longer appeared after shRNA-mediated IRF3 knockout, indicating that the cell's apoptosis response to HT-DNA-induced apoptosis was IRF3 Dependent.
To investigate whether mtp53 can inhibit this apoptotic response, the authors knocked down mtp53 in MDA-MB-231 cells and treated them with HT-DNA.
The results show that HT-DNA treatment can induce apoptosis of about 30% of control cells, and the apoptotic response of mtp53 knockdown cells is more obvious.
In addition, the combination of mtp53 knockout and IRF3 knockout can reduce the apoptotic response to 20%.
Overall, these data indicate that cells expressing mtp53 failed to elicit the cellular innate immune response to cGAS/STING/TBK1/IRF3 pathway activation.
Finally, the authors found that mtp53 can inhibit the formation of the TBK1-STING-IRF3 complex, thus revealing the reason for its negative regulation of innate immune signals from the molecular mechanism level.
In summary, the authors found that Mtp53 interfered with cytoplasmic DNA-mediated cGAS-STING-TBK1-IRF3 signal transmission in the activation of innate immune response.
It reveals the internal reason why tumor cells resist immune surveillance, and does not provide new ideas for future tumor immunotherapy.
(Bioon.
com)
It reveals the internal reason why tumor cells resist immune surveillance, and does not provide new ideas for future tumor immunotherapy.
(Bioon.
com)
Original source: Monisankar Ghosh, Suchandrima Saha, Julie Bettke.
Mutant p53 suppresses innate immune signaling to promote tumorigenesis.
Cancer Cell (2021).
DOI: https://doi.
org/10.
1016/j.
ccell.
2021.
01.
003
Mutant p53 suppresses innate immune signaling to promote tumorigenesis.
Cancer Cell (2021).
DOI: https://doi.
org/10.
1016/j.
ccell.
2021.
01.
003
Next, the author checked whether mtp53 controls IRF3 translocation.
IRF3 is present in the cytoplasm in unstimulated cells, but after activating the STING/TBK1/IRF3 pathway, it transfers to the nucleus.
To evaluate whether mtp53 regulates the subcellular localization of IRF3, the authors stably expressed GFP-IRF3 in H1299 cells with doxycycline-induced mtp53R248W.
In uninduced cells, GFP-IRF3 is present in the cytoplasm.
After HT-DNA treatment, GFP-IRF3 is transferred to the nucleus in about 90% of the cells.
Conversely, mtp53 expression weakened the response of GFP-IRF3 to HT-DNA treatment, and the proportion of GFP-IRF3 in the nucleus was less than 20%.
Comprehensive data show that mtp53 can hinder the nuclear translocation of IRF3.
IRF3 is present in the cytoplasm in unstimulated cells, but after activating the STING/TBK1/IRF3 pathway, it transfers to the nucleus.
To evaluate whether mtp53 regulates the subcellular localization of IRF3, the authors stably expressed GFP-IRF3 in H1299 cells with doxycycline-induced mtp53R248W.
In uninduced cells, GFP-IRF3 is present in the cytoplasm.
After HT-DNA treatment, GFP-IRF3 is transferred to the nucleus in about 90% of the cells.
Conversely, mtp53 expression weakened the response of GFP-IRF3 to HT-DNA treatment, and the proportion of GFP-IRF3 in the nucleus was less than 20%.
Comprehensive data show that mtp53 can hinder the nuclear translocation of IRF3.
Cytoplasmic DNA signals can activate IRF3, which in turn induces the corresponding transcription process.
At the same time, DNA signals also induce IRF3-dependent cell death, that is, IRF3 interacts with BAX and promotes the formation of mitochondrial pores and apoptosis.
The authors found that about 40% of H1299 cells treated with HT-DNA for 24 hours appeared apoptosis, and the above phenomenon no longer appeared after shRNA-mediated IRF3 knockout, indicating that the cell's apoptosis response to HT-DNA-induced apoptosis was IRF3 Dependent.
To investigate whether mtp53 can inhibit this apoptotic response, the authors knocked down mtp53 in MDA-MB-231 cells and treated them with HT-DNA.
The results show that HT-DNA treatment can induce apoptosis of about 30% of control cells, and the apoptotic response of mtp53 knockdown cells is more obvious.
In addition, the combination of mtp53 knockout and IRF3 knockout can reduce the apoptotic response to 20%.
Overall, these data indicate that cells expressing mtp53 failed to elicit the cellular innate immune response to cGAS/STING/TBK1/IRF3 pathway activation.
Finally, the authors found that mtp53 can inhibit the formation of the TBK1-STING-IRF3 complex, thus revealing the reason for its negative regulation of innate immune signals from the molecular mechanism level.
At the same time, DNA signals also induce IRF3-dependent cell death, that is, IRF3 interacts with BAX and promotes the formation of mitochondrial pores and apoptosis.
The authors found that about 40% of H1299 cells treated with HT-DNA for 24 hours appeared apoptosis, and the above phenomenon no longer appeared after shRNA-mediated IRF3 knockout, indicating that the cell's apoptosis response to HT-DNA-induced apoptosis was IRF3 Dependent.
To investigate whether mtp53 can inhibit this apoptotic response, the authors knocked down mtp53 in MDA-MB-231 cells and treated them with HT-DNA.
The results show that HT-DNA treatment can induce apoptosis of about 30% of control cells, and the apoptotic response of mtp53 knockdown cells is more obvious.
In addition, the combination of mtp53 knockout and IRF3 knockout can reduce the apoptotic response to 20%.
Overall, these data indicate that cells expressing mtp53 failed to elicit the cellular innate immune response to cGAS/STING/TBK1/IRF3 pathway activation.
Finally, the authors found that mtp53 can inhibit the formation of the TBK1-STING-IRF3 complex, thus revealing the reason for its negative regulation of innate immune signals from the molecular mechanism level.
In summary, the authors found that Mtp53 interfered with cytoplasmic DNA-mediated cGAS-STING-TBK1-IRF3 signal transmission in the activation of innate immune response.
It reveals the internal reason why tumor cells resist immune surveillance, and does not provide new ideas for future tumor immunotherapy.
(Bioon.
com)
It reveals the internal reason why tumor cells resist immune surveillance, and does not provide new ideas for future tumor immunotherapy.
(Bioon.
com)
Original source: Monisankar Ghosh, Suchandrima Saha, Julie Bettke.
Mutant p53 suppresses innate immune signaling to promote tumorigenesis.
Cancer Cell (2021).
DOI: https://doi.
org/10.
1016/j.
ccell.
2021.
01.
003
Mutant p53 suppresses innate immune signaling to promote tumorigenesis.
Cancer Cell (2021).
DOI: https://doi.
org/10.
1016/j.
ccell.
2021.
01.
003
Cytoplasmic DNA signals can activate IRF3, which in turn induces the corresponding transcription process.
At the same time, DNA signals also induce IRF3-dependent cell death, that is, IRF3 interacts with BAX and promotes the formation of mitochondrial pores and apoptosis.
The authors found that about 40% of H1299 cells treated with HT-DNA for 24 hours appeared apoptosis, and the above phenomenon no longer appeared after shRNA-mediated IRF3 knockout, indicating that the cell's apoptosis response to HT-DNA-induced apoptosis was IRF3 Dependent.
To investigate whether mtp53 can inhibit this apoptotic response, the authors knocked down mtp53 in MDA-MB-231 cells and treated them with HT-DNA.
The results show that HT-DNA treatment can induce apoptosis of about 30% of control cells, and the apoptotic response of mtp53 knockdown cells is more obvious.
In addition, the combination of mtp53 knockout and IRF3 knockout can reduce the apoptotic response to 20%.
Overall, these data indicate that cells expressing mtp53 failed to elicit the cellular innate immune response to cGAS/STING/TBK1/IRF3 pathway activation.
Finally, the authors found that mtp53 can inhibit the formation of the TBK1-STING-IRF3 complex, thus revealing the reason for its negative regulation of innate immune signals from the molecular mechanism level.
At the same time, DNA signals also induce IRF3-dependent cell death, that is, IRF3 interacts with BAX and promotes the formation of mitochondrial pores and apoptosis.
The authors found that about 40% of H1299 cells treated with HT-DNA for 24 hours appeared apoptosis, and the above phenomenon no longer appeared after shRNA-mediated IRF3 knockout, indicating that the cell's apoptosis response to HT-DNA-induced apoptosis was IRF3 Dependent.
To investigate whether mtp53 can inhibit this apoptotic response, the authors knocked down mtp53 in MDA-MB-231 cells and treated them with HT-DNA.
The results show that HT-DNA treatment can induce apoptosis of about 30% of control cells, and the apoptotic response of mtp53 knockdown cells is more obvious.
In addition, the combination of mtp53 knockout and IRF3 knockout can reduce the apoptotic response to 20%.
Overall, these data indicate that cells expressing mtp53 failed to elicit the cellular innate immune response to cGAS/STING/TBK1/IRF3 pathway activation.
Finally, the authors found that mtp53 can inhibit the formation of the TBK1-STING-IRF3 complex, thus revealing the reason for its negative regulation of innate immune signals from the molecular mechanism level.
In summary, the authors found that Mtp53 interfered with cytoplasmic DNA-mediated cGAS-STING-TBK1-IRF3 signal transmission in the activation of innate immune response.
It reveals the internal reason why tumor cells resist immune surveillance, and does not provide new ideas for future tumor immunotherapy.
(Bioon.
com)
It reveals the internal reason why tumor cells resist immune surveillance, and does not provide new ideas for future tumor immunotherapy.
(Bioon.
com)
Original source: Monisankar Ghosh, Suchandrima Saha, Julie Bettke.
Mutant p53 suppresses innate immune signaling to promote tumorigenesis.
Cancer Cell (2021).
DOI: https://doi.
org/10.
1016/j.
ccell.
2021.
01.
003
Mutant p53 suppresses innate immune signaling to promote tumorigenesis.
Cancer Cell (2021).
DOI: https://doi.
org/10.
1016/j.
ccell.
2021.
01.
003
In summary, the authors found that Mtp53 interfered with cytoplasmic DNA-mediated cGAS-STING-TBK1-IRF3 signal transmission in the activation of innate immune response.
It reveals the internal reason why tumor cells resist immune surveillance, and does not provide new ideas for future tumor immunotherapy.
(Bioon.
com)
It reveals the internal reason why tumor cells resist immune surveillance, and does not provide new ideas for future tumor immunotherapy.
(Bioon.
com)
Original source: Monisankar Ghosh, Suchandrima Saha, Julie Bettke.
Mutant p53 suppresses innate immune signaling to promote tumorigenesis.
Cancer Cell (2021).
DOI: https://doi.
org/10.
1016/j.
ccell.
2021.
01.
003
Mutant p53 suppresses innate immune signaling to promote tumorigenesis.
Cancer Cell (2021).
DOI: https://doi.
org/10.
1016/j.
ccell.
2021.
01.
003
Original source: Monisankar Ghosh, Suchandrima Saha, Julie Bettke.
Mutant p53 suppresses innate immune signaling to promote tumorigenesis.
Cancer Cell (2021).
DOI: https://doi.
org/10.
1016/j.
ccell.
2021.
01.
003
：Mutant p53 suppresses innate immune signaling to promote tumorigenesis. Mutant p53 suppresses innate immune signaling to promote tumorigenesis.
Cancer Cell (2021).
DOI: https://doi.
org/10.
1016/j.
ccell.
2021.
01.
003
Cancer Cell
