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p53 Is Regulated in a Biphasic Manner in Hypoxic Human Papillomavirus Type 16 (HPV16)-Positive Cervical Cancer Cells.
- Source :
-
International journal of molecular sciences [Int J Mol Sci] 2020 Dec 15; Vol. 21 (24). Date of Electronic Publication: 2020 Dec 15. - Publication Year :
- 2020
-
Abstract
- Although the effect of hypoxia on p53 in human papillomavirus (HPV)-positive cancer cells has been studied for decades, the impact of p53 regulation on downstream targets and cellular adaptation processes during different periods under hypoxia remains elusive. Here, we show that, despite continuous repression of HPV16 E6/E7 oncogenes, p53 did not instantly recover but instead showed a biphasic regulation marked by further depletion within 24 h followed by an increase at 72 h. Of note, during E6/E7 oncogene suppression, lysosomal degradation antagonizes p53 reconstitution. Consequently, the transcription of p53 responsive genes associated with senescence (e.g., PML and YPEL3 ) cannot be upregulated. In contrast, downstream genes involved in autophagy (e.g., DRAM1 and BNIP3 ) were activated, allowing the evasion of senescence under hypoxic conditions. Hence, dynamic regulation of p53 along with its downstream network of responsive genes favors cellular adaptation and enhances cell survival, although the expression of the viral E6/E7 -oncogenes as drivers for proliferation remained inhibited under hypoxia.
- Subjects :
- Autophagy drug effects
Autophagy genetics
Cell Hypoxia genetics
Cellular Senescence genetics
Down-Regulation
Female
Human papillomavirus 16 genetics
Humans
Lysosomes drug effects
Lysosomes metabolism
Membrane Proteins genetics
Membrane Proteins metabolism
Oncogene Proteins, Viral genetics
Oncogene Proteins, Viral metabolism
Papillomavirus Infections genetics
Promyelocytic Leukemia Protein genetics
Promyelocytic Leukemia Protein metabolism
Proto-Oncogene Proteins genetics
Proto-Oncogene Proteins metabolism
RNA, Small Interfering
Tumor Suppressor Protein p53 genetics
Tumor Suppressor Proteins genetics
Tumor Suppressor Proteins metabolism
Up-Regulation
Uterine Cervical Neoplasms genetics
Uterine Cervical Neoplasms virology
Gene Expression Regulation, Neoplastic genetics
Human papillomavirus 16 metabolism
Papillomavirus Infections metabolism
Tumor Suppressor Protein p53 metabolism
Uterine Cervical Neoplasms metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1422-0067
- Volume :
- 21
- Issue :
- 24
- Database :
- MEDLINE
- Journal :
- International journal of molecular sciences
- Publication Type :
- Academic Journal
- Accession number :
- 33333786
- Full Text :
- https://doi.org/10.3390/ijms21249533