Human papilloma virus E7 oncoprotein abrogates the p53-p21-DREAM pathway

Martin Fischer,Kurt Engeland,Clara Stanko,Sigrid Uxa,Thomas M Magin

doi:10.1038/s41598-017-02831-9

Abstract

High risk human papilloma viruses cause several types of cancer. The HPV oncoproteins E6 and E7 are essential for oncogenic cell transformation. E6 mediates the degradation of the tumor suppressor p53, and E7 can form complexes with the retinoblastoma pRB tumor suppressor. Recently, it has been shown that HPV E7 can also interfere with the function of the DREAM transcriptional repressor complex. Disruption of DREAM-dependent transcriptional repression leads to untimely early expression of central cell cycle regulators. The p53-p21-DREAM pathway represents one important means of cell cycle checkpoint activation by p53. By activating this pathway, p53 can downregulate transcription of genes controlled by DREAM. Here, we present a genome-wide ranked list of genes deregulated by HPV E7 expression and relate it to datasets of cell cycle genes and DREAM targets. We find that DREAM targets are generally deregulated after E7 expression. Furthermore, our analysis shows that p53-dependent downregulation of DREAM targets is abrogated when HPV E7 is expressed. Thus, p53 checkpoint control is impaired by HPV E7 independently of E6. In summary, our analysis reveals that disruption of DREAM through the HPV E7 oncoprotein upregulates most, if not all, cell cycle genes and impairs p53’s control of cell cycle checkpoints.

Highlights

High risk human papilloma viruses (HPV) are oncogenic DNA viruses that can cause cancer of the cervix uteri, oropharynx, penis, vagina, vulva and anus[1,2,3,4]
The mitotic kinase PLK4 is repressed through the p53-p21-DREAM-cycle-dependent elements (CDEs)/cycle genes homology regions (CHRs) pathway[40], and its p53-dependent repression can be abrogated by HPV E741
The HPV E7 oncoprotein deregulates cell cycle genes targeted by the DREAM complex

Summary

Introduction

High risk human papilloma viruses (HPV) are oncogenic DNA viruses that can cause cancer of the cervix uteri, oropharynx, penis, vagina, vulva and anus[1,2,3,4]. The cyclin-dependent kinase (CDK) inhibitor p21 (CDKN1A) is a central mediator of p53 checkpoint control[19, 20], and its function can be impaired by E718, 21, 22 This finding is interesting given that p21 is required for downregulation of genes in response to p5323, 24. NIKS keratinocytes[43] became recently available, we asked whether targets of the p53-p21-DREAM pathway are generally deregulated by HPV E7 on a genome-wide level We integrate these new data with earlier genome-wide datasets that were derived from comparing HPV16/18-infected cervical tumor samples with normal tissue[44, 45], from CaSki cells expressing HPV E2C, a potent transcriptional repressor of E6 and E746, or from HeLa cells in which E6 and E7 were downregulated by RNAi47. In HPV-infected cells, p53 function can be impaired by E7 independently of E6

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