Atypical E2Fs either Counteract or Cooperate with RB during Tumorigenesis Depending on Tissue Context

E2F-transcription factors activate many genes involved in cell cycle progression, DNA repair, and apoptosis. Hence, E2F-dependent transcription must be tightly regulated to prevent tumorigenesis, and therefore metazoan cells possess multiple E2F regulation mechanisms. The best-known is the Retinobla...

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Main Authors: Eva Moreno, Shusil K. Pandit, Mathilda J. M. Toussaint, Laura Bongiovanni, Liesbeth Harkema, Saskia C. van Essen, Elsbeth A. van Liere, Bart Westendorp, Alain de Bruin
Format: Article
Language:English
Published: MDPI AG 2021-04-01
Series:Cancers
Subjects:
Rb
Online Access:https://www.mdpi.com/2072-6694/13/9/2033
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spelling doaj-2effc31911d04836beb4abae7466f3202021-04-23T23:00:33ZengMDPI AGCancers2072-66942021-04-01132033203310.3390/cancers13092033Atypical E2Fs either Counteract or Cooperate with RB during Tumorigenesis Depending on Tissue ContextEva Moreno0Shusil K. Pandit1Mathilda J. M. Toussaint2Laura Bongiovanni3Liesbeth Harkema4Saskia C. van Essen5Elsbeth A. van Liere6Bart Westendorp7Alain de Bruin8Department of Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, 3584 CT Utrecht, The NetherlandsDepartment of Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, 3584 CT Utrecht, The NetherlandsDepartment of Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, 3584 CT Utrecht, The NetherlandsDepartment of Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, 3584 CT Utrecht, The NetherlandsDepartment of Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, 3584 CT Utrecht, The NetherlandsDepartment of Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, 3584 CT Utrecht, The NetherlandsDepartment of Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, 3584 CT Utrecht, The NetherlandsDepartment of Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, 3584 CT Utrecht, The NetherlandsDepartment of Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, 3584 CT Utrecht, The NetherlandsE2F-transcription factors activate many genes involved in cell cycle progression, DNA repair, and apoptosis. Hence, E2F-dependent transcription must be tightly regulated to prevent tumorigenesis, and therefore metazoan cells possess multiple E2F regulation mechanisms. The best-known is the Retinoblastoma protein (RB), which is mutated in many cancers. Atypical E2Fs (E2F7 and −8) can repress E2F-target gene expression independently of RB and are rarely mutated in cancer. Therefore, they may act as emergency brakes in RB-mutated cells to suppress tumor growth. Currently, it is unknown if and how RB and atypical E2Fs functionally interact <i>in vivo</i>. Here, we demonstrate that mice with liver-specific combinatorial deletion of <i>Rb</i> and <i>E2f7/8</i> have reduced life-spans compared to <i>E2f7/8</i> or <i>Rb</i> deletion alone. This was associated with increased proliferation and enhanced malignant progression of liver tumors. Hence, atypical repressor E2Fs and RB cooperatively act as tumor suppressors in hepatocytes. In contrast, loss of either <i>E2f7</i> or <i>E2f8</i> largely prevented the formation of pituitary tumors in <i>Rb<sup>+/−</sup></i> mice. To test whether atypical E2Fs can also function as oncogenes independent of RB loss, we induced long-term overexpression of <i>E2f7</i> or <i>E2f8</i> in mice. E2F7 and −8 overexpression increased the incidence of tumors in the lungs, but not in other tissues. Collectively, these data show that atypical E2Fs can promote but also inhibit tumorigenesis depending on tissue type and RB status. We propose that the complex interactions between atypical E2Fs and RB on maintenance of genetic stability underlie this context-dependency.https://www.mdpi.com/2072-6694/13/9/2033atypical E2FsRbinteractiontumorigenesistransgenic mice
collection DOAJ
language English
format Article
sources DOAJ
author Eva Moreno
Shusil K. Pandit
Mathilda J. M. Toussaint
Laura Bongiovanni
Liesbeth Harkema
Saskia C. van Essen
Elsbeth A. van Liere
Bart Westendorp
Alain de Bruin
spellingShingle Eva Moreno
Shusil K. Pandit
Mathilda J. M. Toussaint
Laura Bongiovanni
Liesbeth Harkema
Saskia C. van Essen
Elsbeth A. van Liere
Bart Westendorp
Alain de Bruin
Atypical E2Fs either Counteract or Cooperate with RB during Tumorigenesis Depending on Tissue Context
Cancers
atypical E2Fs
Rb
interaction
tumorigenesis
transgenic mice
author_facet Eva Moreno
Shusil K. Pandit
Mathilda J. M. Toussaint
Laura Bongiovanni
Liesbeth Harkema
Saskia C. van Essen
Elsbeth A. van Liere
Bart Westendorp
Alain de Bruin
author_sort Eva Moreno
title Atypical E2Fs either Counteract or Cooperate with RB during Tumorigenesis Depending on Tissue Context
title_short Atypical E2Fs either Counteract or Cooperate with RB during Tumorigenesis Depending on Tissue Context
title_full Atypical E2Fs either Counteract or Cooperate with RB during Tumorigenesis Depending on Tissue Context
title_fullStr Atypical E2Fs either Counteract or Cooperate with RB during Tumorigenesis Depending on Tissue Context
title_full_unstemmed Atypical E2Fs either Counteract or Cooperate with RB during Tumorigenesis Depending on Tissue Context
title_sort atypical e2fs either counteract or cooperate with rb during tumorigenesis depending on tissue context
publisher MDPI AG
series Cancers
issn 2072-6694
publishDate 2021-04-01
description E2F-transcription factors activate many genes involved in cell cycle progression, DNA repair, and apoptosis. Hence, E2F-dependent transcription must be tightly regulated to prevent tumorigenesis, and therefore metazoan cells possess multiple E2F regulation mechanisms. The best-known is the Retinoblastoma protein (RB), which is mutated in many cancers. Atypical E2Fs (E2F7 and −8) can repress E2F-target gene expression independently of RB and are rarely mutated in cancer. Therefore, they may act as emergency brakes in RB-mutated cells to suppress tumor growth. Currently, it is unknown if and how RB and atypical E2Fs functionally interact <i>in vivo</i>. Here, we demonstrate that mice with liver-specific combinatorial deletion of <i>Rb</i> and <i>E2f7/8</i> have reduced life-spans compared to <i>E2f7/8</i> or <i>Rb</i> deletion alone. This was associated with increased proliferation and enhanced malignant progression of liver tumors. Hence, atypical repressor E2Fs and RB cooperatively act as tumor suppressors in hepatocytes. In contrast, loss of either <i>E2f7</i> or <i>E2f8</i> largely prevented the formation of pituitary tumors in <i>Rb<sup>+/−</sup></i> mice. To test whether atypical E2Fs can also function as oncogenes independent of RB loss, we induced long-term overexpression of <i>E2f7</i> or <i>E2f8</i> in mice. E2F7 and −8 overexpression increased the incidence of tumors in the lungs, but not in other tissues. Collectively, these data show that atypical E2Fs can promote but also inhibit tumorigenesis depending on tissue type and RB status. We propose that the complex interactions between atypical E2Fs and RB on maintenance of genetic stability underlie this context-dependency.
topic atypical E2Fs
Rb
interaction
tumorigenesis
transgenic mice
url https://www.mdpi.com/2072-6694/13/9/2033
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