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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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 |
work_keys_str_mv |
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