Abstract
The high-risk human papillomavirus (HPV) is the causative agent for cervical cancer. The HPV E7 oncogene promotes S-phase entry from quiescent state in the presence of elevated cell cycle inhibitor p27Kip1, a function that may contribute to carcinogenesis. However, the mechanism by which HPV E7 induces quiescent cells to entry into S-phase is not fully understood. Interestingly, we found that Dyrk1B, a dual-specificity kinase and negative regulator of cell proliferation in quiescent cells, was upregulated in E7 expressing cells. Surprisingly and in contrast to what was previously reported, Dyrk1B played a positive role in S-phase entry of quiescent HPV E7 expressing cells. Mechanistically, Dyrk1B contributed to p27 phosphorylation (at serine 10 and threonine 198), which was important for the proliferation of HPV E7 expressing cells. Moreover, Dyrk1B up-regulated HPV E7. Taken together, our studies uncovered a novel function of Dyrk1B in high-risk HPV E7-mediated cell proliferation. Dyrk1B may serve as a target for therapy in HPV-associated cancers.
Highlights
Human papillomaviruses (HPVs) are small DNA viruses that replicate in squamous epithelia
We investigated the mechanism by which HPV type 16 (HPV-16) E7 abrogates the G0/G1-S cell cycle checkpoint
We showed that the dual-specificity kinase Dyrk1B was upregulated in the high-risk HPV16 E7 expressing cells and played an important role in abrogation of the G0/G1/S checkpoint
Summary
Human papillomaviruses (HPVs) are small DNA viruses that replicate in squamous epithelia. Specific types of HPV (high-risk HPVs) are the causative agents for cervical and several other cancers [1]. HPV infection normally initiates in the basal layer of the squamous epithelia and HPV genome is maintained in the basal cells. Epithelial cells infected by HPV type 16 (HPV-16), which is the cause of approximately 50% of cervical cancers worldwide, retain the ability to stratify but lose their ability to differentiate morphologically [2]. HPV can manipulate the cell cycle by establishing a milieu in the differentiated keratinocytes supportive for viral DNA amplification. HPV E7 plays an important role during the viral life cycle and the E7s encoded by high-risk HPV types contribute to the development of cancers
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