p53-Dependent Nestin Regulation Links Tumor Suppression to Cellular Plasticity in Liver Cancer

Darjus F Tschaharganeh; Wen Xue; Diego F Calvisi; Matthias Evert; Tatyana V Michurina; Lukas E Dow; Ana Banito; Sarah F Katz; Edward R Kastenhuber; Susann Weissmueller; Chun-Hao Huang; Andre Lechel; Jesper Bøje Andersen; David Capper; Lars Zender; Thomas Longerich; Grigori Enikolopov; Scott W Lowe

doi:10.1016/j.cell.2014.05.051

p53-Dependent Nestin Regulation Links Tumor Suppression to Cellular Plasticity in Liver Cancer

Darjus F Tschaharganeh, Wen Xue, Diego F Calvisi, Matthias Evert, Tatyana V Michurina, Lukas E Dow, Ana Banito, Sarah F Katz, Edward R Kastenhuber, Susann Weissmueller, Chun-Hao Huang, Andre Lechel, Jesper Bøje Andersen, David Capper, Lars Zender, Thomas Longerich, Grigori Enikolopov, Scott W Lowe

104 Citations (Scopus)

Abstract

The p53 tumor suppressor coordinates a series of antiproliferative responses that restrict the expansion of malignant cells, and as a consequence, p53 is lost or mutated in the majority of human cancers. Here, we show that p53 restricts expression of the stem and progenitor-cell-associated protein nestin in an Sp1/3 transcription-factor-dependent manner and that Nestin is required for tumor initiation in vivo. Moreover, loss of p53 facilitates dedifferentiation of mature hepatocytes into nestin-positive progenitor-like cells, which are poised to differentiate into hepatocellular carcinomas (HCCs) or cholangiocarcinomas (CCs) in response to lineage-specific mutations that target Wnt and Notch signaling, respectively. Many human HCCs and CCs show elevated nestin expression, which correlates with p53 loss of function and is associated with decreased patient survival. Therefore, transcriptional repression of Nestin by p53 restricts cellular plasticity and tumorigenesis in liver cancer.

Original language	English
Journal	Cell
Volume	158
Issue number	3
Pages (from-to)	579-92
Number of pages	14
ISSN	0092-8674
DOIs	https://doi.org/10.1016/j.cell.2014.05.051
Publication status	Published - 31 Jul 2014

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Tschaharganeh, D. F., Xue, W., Calvisi, D. F., Evert, M., Michurina, T. V., Dow, L. E., Banito, A., Katz, S. F., Kastenhuber, E. R., Weissmueller, S., Huang, C-H., Lechel, A., Andersen, J. B., Capper, D., Zender, L., Longerich, T., Enikolopov, G., & Lowe, S. W. (2014). p53-Dependent Nestin Regulation Links Tumor Suppression to Cellular Plasticity in Liver Cancer. Cell, 158(3), 579-92. https://doi.org/10.1016/j.cell.2014.05.051

Tschaharganeh, DF, Xue, W, Calvisi, DF, Evert, M, Michurina, TV, Dow, LE, Banito, A, Katz, SF, Kastenhuber, ER, Weissmueller, S, Huang, C-H, Lechel, A, Andersen, JB, Capper, D, Zender, L, Longerich, T, Enikolopov, G & Lowe, SW 2014, 'p53-Dependent Nestin Regulation Links Tumor Suppression to Cellular Plasticity in Liver Cancer', Cell, vol. 158, no. 3, pp. 579-92. https://doi.org/10.1016/j.cell.2014.05.051

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title = "p53-Dependent Nestin Regulation Links Tumor Suppression to Cellular Plasticity in Liver Cancer",

abstract = "The p53 tumor suppressor coordinates a series of antiproliferative responses that restrict the expansion of malignant cells, and as a consequence, p53 is lost or mutated in the majority of human cancers. Here, we show that p53 restricts expression of the stem and progenitor-cell-associated protein nestin in an Sp1/3 transcription-factor-dependent manner and that Nestin is required for tumor initiation in vivo. Moreover, loss of p53 facilitates dedifferentiation of mature hepatocytes into nestin-positive progenitor-like cells, which are poised to differentiate into hepatocellular carcinomas (HCCs) or cholangiocarcinomas (CCs) in response to lineage-specific mutations that target Wnt and Notch signaling, respectively. Many human HCCs and CCs show elevated nestin expression, which correlates with p53 loss of function and is associated with decreased patient survival. Therefore, transcriptional repression of Nestin by p53 restricts cellular plasticity and tumorigenesis in liver cancer.",

author = "Tschaharganeh, {Darjus F} and Wen Xue and Calvisi, {Diego F} and Matthias Evert and Michurina, {Tatyana V} and Dow, {Lukas E} and Ana Banito and Katz, {Sarah F} and Kastenhuber, {Edward R} and Susann Weissmueller and Chun-Hao Huang and Andre Lechel and Andersen, {Jesper B{\o}je} and David Capper and Lars Zender and Thomas Longerich and Grigori Enikolopov and Lowe, {Scott W}",

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AU - Tschaharganeh, Darjus F

AU - Xue, Wen

AU - Calvisi, Diego F

AU - Evert, Matthias

AU - Michurina, Tatyana V

AU - Dow, Lukas E

AU - Banito, Ana

AU - Katz, Sarah F

AU - Kastenhuber, Edward R

AU - Weissmueller, Susann

AU - Huang, Chun-Hao

AU - Lechel, Andre

AU - Andersen, Jesper Bøje

AU - Capper, David

AU - Zender, Lars

AU - Longerich, Thomas

AU - Enikolopov, Grigori

AU - Lowe, Scott W

PY - 2014/7/31

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N2 - The p53 tumor suppressor coordinates a series of antiproliferative responses that restrict the expansion of malignant cells, and as a consequence, p53 is lost or mutated in the majority of human cancers. Here, we show that p53 restricts expression of the stem and progenitor-cell-associated protein nestin in an Sp1/3 transcription-factor-dependent manner and that Nestin is required for tumor initiation in vivo. Moreover, loss of p53 facilitates dedifferentiation of mature hepatocytes into nestin-positive progenitor-like cells, which are poised to differentiate into hepatocellular carcinomas (HCCs) or cholangiocarcinomas (CCs) in response to lineage-specific mutations that target Wnt and Notch signaling, respectively. Many human HCCs and CCs show elevated nestin expression, which correlates with p53 loss of function and is associated with decreased patient survival. Therefore, transcriptional repression of Nestin by p53 restricts cellular plasticity and tumorigenesis in liver cancer.

AB - The p53 tumor suppressor coordinates a series of antiproliferative responses that restrict the expansion of malignant cells, and as a consequence, p53 is lost or mutated in the majority of human cancers. Here, we show that p53 restricts expression of the stem and progenitor-cell-associated protein nestin in an Sp1/3 transcription-factor-dependent manner and that Nestin is required for tumor initiation in vivo. Moreover, loss of p53 facilitates dedifferentiation of mature hepatocytes into nestin-positive progenitor-like cells, which are poised to differentiate into hepatocellular carcinomas (HCCs) or cholangiocarcinomas (CCs) in response to lineage-specific mutations that target Wnt and Notch signaling, respectively. Many human HCCs and CCs show elevated nestin expression, which correlates with p53 loss of function and is associated with decreased patient survival. Therefore, transcriptional repression of Nestin by p53 restricts cellular plasticity and tumorigenesis in liver cancer.

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SP - 579

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JO - Cell

JF - Cell

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p53-Dependent Nestin Regulation Links Tumor Suppression to Cellular Plasticity in Liver Cancer

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