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Atypical E2Fs either Counteract or Cooperate with RB during Tumorigenesis Depending on Tissue Context
- Source :
- Cancers, Cancers, 13(9):2033. MDPI AG, Cancers, 13(9), 1. Multidisciplinary Digital Publishing Institute (MDPI), Volume 13, Issue 9, Cancers, Vol 13, Iss 2033, p 2033 (2021)
- Publication Year :
- 2021
-
Abstract
- Simple SummaryIn virtually all human malignancies, the CDK-RB-E2F pathway is dysregulated resulting in the activation of the E2F transcriptional network. Rb and atypical E2Fs are the most important negative regulators of E2F-dependent transcription during tumorigenesis. However, it is unknown whether they cooporate or act independently in tumor development. Here we show that combined loss of RB and atypical E2Fs in mice enhances tumorigenesis in the liver, while in the pituitary gland, we observe inhibition of tumorigenesis. These findings suggest that the interaction between RB and atypical E2Fs in controlling tumorigenesis occurs in a tissue cell-type specific manner.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 in vivo. Here, we demonstrate that mice with liver-specific combinatorial deletion of Rb and E2f7/8 have reduced life-spans compared to E2f7/8 or Rb 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 E2f7 or E2f8 largely prevented the formation of pituitary tumors in Rb+/- mice. To test whether atypical E2Fs can also function as oncogenes independent of RB loss, we induced long-term overexpression of E2f7 or E2f8 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.
- Subjects :
- 0301 basic medicine
Genetically modified mouse
EXPRESSION
Cancer Research
Interaction
DNA repair
Repressor
interaction
Context (language use)
ORGANIZATION
transgenic mice
medicine.disease_cause
Article
03 medical and health sciences
0302 clinical medicine
medicine
Transgenic mice
CELL-CYCLE
RETINOBLASTOMA PROTEIN
TRANSCRIPTION
E2F
Rb
RC254-282
ARREST
biology
MUTATIONS
Retinoblastoma protein
Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Cell cycle
GENE
Atypical E2Fs
atypical E2Fs
tumorigenesis
030104 developmental biology
Oncology
030220 oncology & carcinogenesis
FAMILY-MEMBER
Tumorigenesis
ENTRY
Cancer research
biology.protein
biological phenomena, cell phenomena, and immunity
Carcinogenesis
Subjects
Details
- ISSN :
- 20726694
- Volume :
- 13
- Issue :
- 9
- Database :
- OpenAIRE
- Journal :
- Cancers
- Accession number :
- edsair.doi.dedup.....a0f52c3e75cfcd006846fa9cd491a173