p21 produces a bioactive secretome that places stressed cells under immunosurveillance

Ines Sturmlechner; Cheng Zhang; Chance C. Sine; Erik Jan van Deursen; Karthik B. Jeganathan; Naomi Hamada; Jan Grasic; David Friedman; Jeremy T. Stutchman; Ismail Can; Masakazu Hamada; Do Young Lim; Jeong Heon Lee; Tamas Ordog; Remi Martin Laberge; Virginia Shapiro; Darren J. Baker; Hu Li; Jan M. van Deursen

doi:10.1126/science.abb3420

p21 produces a bioactive secretome that places stressed cells under immunosurveillance

Ines Sturmlechner, Cheng Zhang, Chance C. Sine, Erik Jan van Deursen, Karthik B. Jeganathan, Naomi Hamada, Jan Grasic, David Friedman, Jeremy T. Stutchman, Ismail Can, Masakazu Hamada, Do Young Lim, Jeong Heon Lee, Tamas Ordog, Remi Martin Laberge, Virginia Shapiro, Darren J. Baker, Hu Li, Jan M. van Deursen

Research output: Contribution to journal › Article › peer-review

Abstract

Immune cells identify and destroy damaged cells to prevent them from causing cancer or other pathologies by mechanisms that remain poorly understood. Here, we report that the cell-cycle inhibitor p21 places cells under immunosurveillance to establish a biological timer mechanism that controls cell fate. p21 activates retinoblastoma protein (Rb)-dependent transcription at select gene promoters to generate a complex bioactive secretome, termed p21-activated secretory phenotype (PASP). The PASP includes the chemokine CXCL14, which promptly attracts macrophages. These macrophages disengage if cells normalize p21 within 4 days, but if p21 induction persists, they polarize toward an M1 phenotype and lymphocytes mount a cytotoxic T cell response to eliminate target cells, including preneoplastic cells. Thus, p21 concurrently induces proliferative arrest and immunosurveillance of cells under duress.

Original language	English (US)
Article number	eabb3420
Journal	Science
Volume	374
Issue number	6567
DOIs	https://doi.org/10.1126/science.abb3420
State	Published - Oct 29 2021

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Sturmlechner, I., Zhang, C., Sine, C. C., van Deursen, E. J., Jeganathan, K. B., Hamada, N., Grasic, J., Friedman, D., Stutchman, J. T., Can, I., Hamada, M., Lim, D. Y., Lee, J. H., Ordog, T., Laberge, R. M., Shapiro, V., Baker, D. J., Li, H., & van Deursen, J. M. (2021). p21 produces a bioactive secretome that places stressed cells under immunosurveillance. Science, 374(6567), Article eabb3420. https://doi.org/10.1126/science.abb3420

Sturmlechner, I, Zhang, C, Sine, CC, van Deursen, EJ, Jeganathan, KB, Hamada, N, Grasic, J, Friedman, D, Stutchman, JT, Can, I, Hamada, M, Lim, DY, Lee, JH , Ordog, T, Laberge, RM, Shapiro, V , Baker, DJ , Li, H & van Deursen, JM 2021, 'p21 produces a bioactive secretome that places stressed cells under immunosurveillance', Science, vol. 374, no. 6567, eabb3420. https://doi.org/10.1126/science.abb3420

@article{26b73d224f2349d0b3fc3dd9893a0b70,

title = "p21 produces a bioactive secretome that places stressed cells under immunosurveillance",

abstract = "Immune cells identify and destroy damaged cells to prevent them from causing cancer or other pathologies by mechanisms that remain poorly understood. Here, we report that the cell-cycle inhibitor p21 places cells under immunosurveillance to establish a biological timer mechanism that controls cell fate. p21 activates retinoblastoma protein (Rb)-dependent transcription at select gene promoters to generate a complex bioactive secretome, termed p21-activated secretory phenotype (PASP). The PASP includes the chemokine CXCL14, which promptly attracts macrophages. These macrophages disengage if cells normalize p21 within 4 days, but if p21 induction persists, they polarize toward an M1 phenotype and lymphocytes mount a cytotoxic T cell response to eliminate target cells, including preneoplastic cells. Thus, p21 concurrently induces proliferative arrest and immunosurveillance of cells under duress.",

author = "Ines Sturmlechner and Cheng Zhang and Sine, {Chance C.} and {van Deursen}, {Erik Jan} and Jeganathan, {Karthik B.} and Naomi Hamada and Jan Grasic and David Friedman and Stutchman, {Jeremy T.} and Ismail Can and Masakazu Hamada and Lim, {Do Young} and Lee, {Jeong Heon} and Tamas Ordog and Laberge, {Remi Martin} and Virginia Shapiro and Baker, {Darren J.} and Hu Li and {van Deursen}, {Jan M.}",

note = "Publisher Copyright: Copyright {\textcopyright} 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works",

year = "2021",

month = oct,

day = "29",

doi = "10.1126/science.abb3420",

language = "English (US)",

volume = "374",

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AU - Sturmlechner, Ines

AU - Zhang, Cheng

AU - Sine, Chance C.

AU - van Deursen, Erik Jan

AU - Jeganathan, Karthik B.

AU - Hamada, Naomi

AU - Grasic, Jan

AU - Friedman, David

AU - Stutchman, Jeremy T.

AU - Can, Ismail

AU - Hamada, Masakazu

AU - Lim, Do Young

AU - Lee, Jeong Heon

AU - Ordog, Tamas

AU - Laberge, Remi Martin

AU - Shapiro, Virginia

AU - Baker, Darren J.

AU - Li, Hu

AU - van Deursen, Jan M.

PY - 2021/10/29

Y1 - 2021/10/29

N2 - Immune cells identify and destroy damaged cells to prevent them from causing cancer or other pathologies by mechanisms that remain poorly understood. Here, we report that the cell-cycle inhibitor p21 places cells under immunosurveillance to establish a biological timer mechanism that controls cell fate. p21 activates retinoblastoma protein (Rb)-dependent transcription at select gene promoters to generate a complex bioactive secretome, termed p21-activated secretory phenotype (PASP). The PASP includes the chemokine CXCL14, which promptly attracts macrophages. These macrophages disengage if cells normalize p21 within 4 days, but if p21 induction persists, they polarize toward an M1 phenotype and lymphocytes mount a cytotoxic T cell response to eliminate target cells, including preneoplastic cells. Thus, p21 concurrently induces proliferative arrest and immunosurveillance of cells under duress.

AB - Immune cells identify and destroy damaged cells to prevent them from causing cancer or other pathologies by mechanisms that remain poorly understood. Here, we report that the cell-cycle inhibitor p21 places cells under immunosurveillance to establish a biological timer mechanism that controls cell fate. p21 activates retinoblastoma protein (Rb)-dependent transcription at select gene promoters to generate a complex bioactive secretome, termed p21-activated secretory phenotype (PASP). The PASP includes the chemokine CXCL14, which promptly attracts macrophages. These macrophages disengage if cells normalize p21 within 4 days, but if p21 induction persists, they polarize toward an M1 phenotype and lymphocytes mount a cytotoxic T cell response to eliminate target cells, including preneoplastic cells. Thus, p21 concurrently induces proliferative arrest and immunosurveillance of cells under duress.

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p21 produces a bioactive secretome that places stressed cells under immunosurveillance

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