E6AP promotes the degradation of the PML tumor suppressor

I. Louria-Hayon; O. Alsheich-Bartok; Y. Levav-Cohen; I. Silberman; M. Berger; T. Grossman; K. Matentzoglu; Y. H. Jiang; S. Muller; M. Scheffner; S. Haupt; Y. Haupt

doi:10.1038/cdd.2009.31

E6AP promotes the degradation of the PML tumor suppressor

I. Louria-Hayon, O. Alsheich-Bartok, Y. Levav-Cohen, I. Silberman, M. Berger, T. Grossman, K. Matentzoglu, Y. H. Jiang, S. Muller, M. Scheffner, S. Haupt, Y. Haupt^*

^*Corresponding author for this work

Department of Immunology and Cancer Research

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

79 Scopus citations

Abstract

The promyelocytic leukemia (PML) tumor suppressor is essential for the formation of PML nuclear bodies (NBs). PML and PML-NBs have been implicated in the regulation of growth inhibition, senescence and apoptosis. PML is activated in response to stress signals and is downregulated in certain human cancers. However, the factors mediating PML stability are incompletely understood. Here we demonstrate that a catalytically active form of the mammalian E3 ligase E6AP (HPV E6-associated protein) acts to reduce the half-life of the PML protein by promoting its degradation in the proteasome. E6AP mediates the ubiquitination of PML in an in vitro ubiquitination assay. E6AP and PML interact at physiological levels and colocalize in PML-NBs. Importantly, PML protein expression is elevated in multiple organs and cell types from E6AP null mice and in lymphoid cells is associated with increased number and intensity of PML-NBs. This PML elevation is enhanced in response to DNA damage. Our results identify E6AP as an important regulator of PML and PML-NBs.

Original language	English
Pages (from-to)	1156-1166
Number of pages	11
Journal	Cell Death and Differentiation
Volume	16
Issue number	8
DOIs	https://doi.org/10.1038/cdd.2009.31
State	Published - 2009

Bibliographical note

Funding Information:
Acknowledgements. We thank Z Nawaz, A Ben-Zeev, D Trono, L Banks and PP Pandolfi for their generous gifts of expression plasmids; A Beaudet for the E6AP KO mice; and PP Pandolfi for the PML KO MEFs. This work was supported by grants from the Association for International Cancer Research, the German-Israeli Foundation for Scientific Research and Development, the Israel Science Foundation (grant no. 1341/05), the Australian National Health and Medical Research Council to YH (no. 509196), and by the Active p53 project within the 6th framework program of the European Commission (contract 503576). The content of this publication reflects the author’s views. European Commission is not liable for any that may be made of this information.

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10.1038/cdd.2009.31

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@article{2591c2ac29b74ada8ff6ce9a3d5999e2,

title = "E6AP promotes the degradation of the PML tumor suppressor",

abstract = "The promyelocytic leukemia (PML) tumor suppressor is essential for the formation of PML nuclear bodies (NBs). PML and PML-NBs have been implicated in the regulation of growth inhibition, senescence and apoptosis. PML is activated in response to stress signals and is downregulated in certain human cancers. However, the factors mediating PML stability are incompletely understood. Here we demonstrate that a catalytically active form of the mammalian E3 ligase E6AP (HPV E6-associated protein) acts to reduce the half-life of the PML protein by promoting its degradation in the proteasome. E6AP mediates the ubiquitination of PML in an in vitro ubiquitination assay. E6AP and PML interact at physiological levels and colocalize in PML-NBs. Importantly, PML protein expression is elevated in multiple organs and cell types from E6AP null mice and in lymphoid cells is associated with increased number and intensity of PML-NBs. This PML elevation is enhanced in response to DNA damage. Our results identify E6AP as an important regulator of PML and PML-NBs.",

author = "I. Louria-Hayon and O. Alsheich-Bartok and Y. Levav-Cohen and I. Silberman and M. Berger and T. Grossman and K. Matentzoglu and Jiang, {Y. H.} and S. Muller and M. Scheffner and S. Haupt and Y. Haupt",

note = "Funding Information: Acknowledgements. We thank Z Nawaz, A Ben-Zeev, D Trono, L Banks and PP Pandolfi for their generous gifts of expression plasmids; A Beaudet for the E6AP KO mice; and PP Pandolfi for the PML KO MEFs. This work was supported by grants from the Association for International Cancer Research, the German-Israeli Foundation for Scientific Research and Development, the Israel Science Foundation (grant no. 1341/05), the Australian National Health and Medical Research Council to YH (no. 509196), and by the Active p53 project within the 6th framework program of the European Commission (contract 503576). The content of this publication reflects the author{\textquoteright}s views. European Commission is not liable for any that may be made of this information.",

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AU - Louria-Hayon, I.

AU - Alsheich-Bartok, O.

AU - Levav-Cohen, Y.

AU - Silberman, I.

AU - Berger, M.

AU - Grossman, T.

AU - Matentzoglu, K.

AU - Jiang, Y. H.

AU - Muller, S.

AU - Scheffner, M.

AU - Haupt, S.

AU - Haupt, Y.

N1 - Funding Information: Acknowledgements. We thank Z Nawaz, A Ben-Zeev, D Trono, L Banks and PP Pandolfi for their generous gifts of expression plasmids; A Beaudet for the E6AP KO mice; and PP Pandolfi for the PML KO MEFs. This work was supported by grants from the Association for International Cancer Research, the German-Israeli Foundation for Scientific Research and Development, the Israel Science Foundation (grant no. 1341/05), the Australian National Health and Medical Research Council to YH (no. 509196), and by the Active p53 project within the 6th framework program of the European Commission (contract 503576). The content of this publication reflects the author’s views. European Commission is not liable for any that may be made of this information.

PY - 2009

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N2 - The promyelocytic leukemia (PML) tumor suppressor is essential for the formation of PML nuclear bodies (NBs). PML and PML-NBs have been implicated in the regulation of growth inhibition, senescence and apoptosis. PML is activated in response to stress signals and is downregulated in certain human cancers. However, the factors mediating PML stability are incompletely understood. Here we demonstrate that a catalytically active form of the mammalian E3 ligase E6AP (HPV E6-associated protein) acts to reduce the half-life of the PML protein by promoting its degradation in the proteasome. E6AP mediates the ubiquitination of PML in an in vitro ubiquitination assay. E6AP and PML interact at physiological levels and colocalize in PML-NBs. Importantly, PML protein expression is elevated in multiple organs and cell types from E6AP null mice and in lymphoid cells is associated with increased number and intensity of PML-NBs. This PML elevation is enhanced in response to DNA damage. Our results identify E6AP as an important regulator of PML and PML-NBs.

AB - The promyelocytic leukemia (PML) tumor suppressor is essential for the formation of PML nuclear bodies (NBs). PML and PML-NBs have been implicated in the regulation of growth inhibition, senescence and apoptosis. PML is activated in response to stress signals and is downregulated in certain human cancers. However, the factors mediating PML stability are incompletely understood. Here we demonstrate that a catalytically active form of the mammalian E3 ligase E6AP (HPV E6-associated protein) acts to reduce the half-life of the PML protein by promoting its degradation in the proteasome. E6AP mediates the ubiquitination of PML in an in vitro ubiquitination assay. E6AP and PML interact at physiological levels and colocalize in PML-NBs. Importantly, PML protein expression is elevated in multiple organs and cell types from E6AP null mice and in lymphoid cells is associated with increased number and intensity of PML-NBs. This PML elevation is enhanced in response to DNA damage. Our results identify E6AP as an important regulator of PML and PML-NBs.

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E6AP promotes the degradation of the PML tumor suppressor

Abstract

Bibliographical note

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