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E6 oncoprotein derived from high-risk human papillomavirus (HPV) drives the development of cervical cancer through p53 degradation. Because cervical cancer therapies to inactivate HPV or E6 protein are not available, alternative strategies are required. Here, we show that HPV-mediated nuclear export of human heterochromatin protein 1γ (HP1γ) reduces the stability of p53 through UBE2L3-mediated p53 polyubiquitination during cervical cancer progression. In general, HP1 plays a key role in heterochromatin formation and transcription in the nucleus. However, our immunostaining data showed that the majority of HP1γ is localized in the cytoplasm in HPV-mediated cervical cancer. We found that HPV E6 protein drives unusual nuclear export of HP1γ through the interaction between the NES sequence of HP1γ and exportin-1. The mutation of the NES sequence in HP1γ led to nuclear retention of HP1γ and reduced cervical cancer cell growth and tumor generation. We further discovered that HP1γ directly suppresses the expression of UBE2L3 which drives E6-mediated proteasomal degradation of p53 in cervical cancer. Downregulation of UBE2L3 by overexpression of HP1γ suppressed UBE2L3-dependent p53 degradation-promoting apoptosis of cervical cancer cells. Our findings propose a useful strategy to overcome p53 degradation in cervical cancer through the blockage of nuclear export of HP1γ.
This article was published in the following journal.
Name: Cell death and differentiation
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Although inhibitor of differentiation 1 (Id‑1) and NF‑κB have been shown have play a role in tumorigenesis, their mechanisms and exact roles in cervical cancer have not yet been addressed. This s...
Export of mRNA from the nucleus to the cytoplasm is a critical process for all eukaryotic gene expression. As mRNA is synthesized, it is packaged with a myriad of RNA-binding proteins to form ribonucl...
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mRNA is the "hermes" of gene expression as it carries the information of a protein-coding gene to the ribosome. Already during its synthesis, the mRNA is bound by mRNA-binding proteins that package th...
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Cervical cancer the most frequent neoplasm and the fifth mortality rate of malignancies of the women in the world. It results in about 1,000 women in Taiwan and about 200,000 women worldwi...
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Specific amino acid sequences present in the primary amino acid sequence of proteins which mediate their export from the CELL NUCLEUS. They are rich in hydrophobic residues, such as LEUCINE and ISOLEUCINE.
The techniques involved in creating and inserting synthetic selfish genetic elements called gene drives. Gene drives carry a "payload gene" and are designed to increase in frequency in the population over time, eventually to all members of the population.
A network of nerve fibers originating in the upper four cervical spinal cord segments. The cervical plexus distributes cutaneous nerves to parts of the neck, shoulders, and back of the head, and motor fibers to muscles of the cervical spinal column, infrahyoid muscles, and the diaphragm.
A parameter usually used in PRENATAL ULTRASONOGRAPHY to measure the length of the uterine neck (CERVIX UTERI). Cervical length or its shortening is used to identify and prevent early cervical opening and PRETERM BIRTH.
A heterogeneous ribonucleoprotein that contains an RNA-BINDING MOTIF and has poly(ADP)ribose-binding capability. It functions in the packaging of pre-mRNA into hnRNP particles for export to the cytoplasm and may play a role in RNA SPLICING site selection.
Cervical cancer is a malignant neoplasm of the cervix uteri or cervical area. Symptoms include vaginal bleeding, but may not present until later stages of the cancer. Cervical cancer can be treated using surgery (including local excision) in early stages...