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Inactivating E2f1 reverts apoptosis resistance and cancer sensitivity in Trp53-deficient mice
Norbert M Wikonkal1, Eva Remenyik, Dejan Knezevic
1Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT 06520 USA.
Abstract:
The E2f1 transcription factor, which regulates genes required for S-phase entry, also induces apoptosis by transcriptional and post-translational mechanisms. As E2f1 is inducible by DNA damage we investigated its importance in vivo in ultraviolet (UV)-induced apoptosis, a protective mechanism that prevents the epidermis from accumulating UV-induced mutations. Contrary to expectation, E2f1-/- mice demonstrated enhanced keratinocyte apoptosis after UVB exposure, whereas apoptosis was suppressed by epidermis-specific overexpression of human E2F1. Apoptosis induced by -radiation was also repressed by E2f1. E2f1-/-;Trp53-/- double knockout mice exhibited the elevated UVB-induced apoptosis of E2f1-/- alone, rather than the profound apoptosis defect seen in Trp53-/- mice, indicating that Trp53 (p53) lies functionally upstream of E2f1. Transfecting E2F1 into E2f1-/-;Trp53-/- primary fibroblasts suppressed UVB-induced apoptosis and this suppression was relieved by Trp53. The double knockout also reverted the abnormal sex ratio and early-onset tumours of Trp53-/- mice. These results imply that E2f1 functions as a suppressor of an apoptosis pathway that is initiated by DNA photoproducts and perhaps genetic abnormalities; p53 relieves this suppression.
Insights
The transcription factor E2f1 normally suppresses DNA damage-induced apoptosis. Loss of E2f1 enhances apoptosis, while p53 acts upstream to relieve this suppression, impacting cell survival and tumor suppression.
Area of Science:
- Molecular Biology
- Genetics
- Cell Biology
Background:
- E2f1 transcription factor regulates cell cycle and apoptosis.
- DNA damage, such as UV radiation, can induce apoptosis.
- The role of E2f1 in DNA damage-induced apoptosis was previously unclear.
Purpose of the Study:
- Investigate the in vivo role of E2f1 in UV-induced apoptosis.
- Determine the relationship between E2f1 and p53 in apoptosis pathways.
- Understand E2f1's function in epidermal protection against UV damage.
Main Methods:
- Utilized E2f1 knockout (E2f1-/-) mice and double knockout (E2f1-/-;Trp53-/-) mice.
- Examined keratinocyte apoptosis after UVB exposure.
- Overexpressed human E2F1 in epidermis-specific manner.
- Performed transfections of E2F1 into primary fibroblasts.
Main Results:
- E2f1-/- mice showed enhanced UVB-induced keratinocyte apoptosis.
- Epidermal E2F1 overexpression suppressed UV-induced apoptosis.
- p53 (Trp53) functions upstream of E2f1 in the apoptosis pathway.
- E2f1 suppresses an apoptosis pathway, with p53 relieving this suppression.
Conclusions:
- E2f1 acts as a suppressor of DNA damage-induced apoptosis.
- p53 modulates E2f1's apoptotic function, particularly in response to UV radiation.
- E2f1 and p53 play critical roles in preventing mutations and tumor formation after DNA damage.