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

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

doi:10.1038/s41598-017-02831-9

Cited by 80 publications

(56 citation statements)

References 61 publications

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“…Thus, the effect of HPV E6/E7 on TMPOP2 expression might be mediated by cellular transcription factors. It was previously shown that high-risk HPV E6 cooperates with E6AP to promote p53 degradation and that HPV E7 impairs the repressive activity of the p53-p21-DREAM pathway (20), which consequently alter the expression of p53 target genes. As shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

Human Papillomavirus E6/E7 and Long Noncoding RNA TMPOP2 Mutually Upregulated Gene Expression in Cervical Cancer Cells

Liu

et al. 2019

J Virol

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TMPOP2 was previously suggested to be an oncogenic long noncoding RNA which is excessively expressed in cervical cancer cells and inhibits E-cadherin gene expression by recruiting transcription repressor EZH2 to the gene promoter. So far, the function and regulation of TMPOP2 in cervical cancer remain largely unknown. Herein, we found that TMPOP2 expression was correlated with human papillomavirus 16/18 (HPV16/18) E6 and E7 in cervical cancer cell lines CaSki and HeLa. Tumor suppressor p53, which is targeted for degradation by HPV16/18, was demonstrated to associate with two p53 response elements in the TMPOP2 promoter to repress the transcription of the TMPOP2 gene. Reciprocally, ectopic expression of TMPOP2 was demonstrated to sequester tumor repressor microRNAs (miRNAs) miR-375 and miR-139 which target HPV16/18 E6/E7 mRNA and resulted in an upregulation of HPV16/18 E6/E7 genes. Thereby, HPV16/18 E6/E7 and the long noncoding RNA (lncRNA) TMPOP2 form a positive feedback loop to mutually derepress gene expression in cervical cancer cells. Moreover, results of RNA sequencing and cell cycle analysis showed that knockdown of TMPOP2 impaired the expression of cell cycle genes, induced cell cycle arrest, and inhibited HeLa cell proliferation. Together, our results indicate that TMPOP2 and HPV16/18 E6/E7 mutually strengthen their expression in cervical cancer cells to enhance tumorigenic activities. IMPORTANCE Human papillomaviruses 16 and 18 (HPV16/18) are the main causative agents of cervical cancer. Viral proteins HPV16/18 E6 and E7 are constitutively expressed in cancer cells to maintain oncogenic phenotypes. Accumulating evidences suggest that HPVs are correlated with the deregulation of long noncoding RNAs (lncRNAs) in cervical cancer, although the mechanism was unexplored in most cases. TMPOP2 is a newly identified lncRNA excessively expressed in cervical cancer. However, the mechanism for the upregulation of TMPOP2 in cervical cancer cells remains largely unknown and its relationship with HPVs is still elusive. The significance of our research is in revealing the mutual upregulation of HPV16/18 E6/E7 and TMPOP2 with the molecular mechanisms explored. This study will expand our understandings of the oncogenic activities of human papillomaviruses and lncRNAs. KEYWORDS HPV E6/E7, cervical cancer, lncRNA TMPOP2, miRNAs, p53 H igh-risk human papillomaviruses (HPVs), primarily including HPV16 and HPV18, are causative agents of cervical cancer, which is one of the leading lethal female cancers worldwide. Integration of HPV DNA into the host cell genome results in the constitutive high expression of two viral oncogenes, HPV E6 and E7, under the control of cellular transcription factors. Viral protein E6 promotes p53 protein degradation FIG 4 TMPOP2 reciprocally regulated the expression of HPV E6/E7 in cervical cancer cells. (A) The efficacy of TMPOP2 knockdown in HeLa cells. (B)The protein levels of HPV18 E6/E7 were decreased following TMPOP2 knockdown. GAPDH was the protein loading control. (C) The mRNA levels of HPV1...

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Section: Resultsmentioning

confidence: 99%

Human Papillomavirus E6/E7 and Long Noncoding RNA TMPOP2 Mutually Upregulated Gene Expression in Cervical Cancer Cells

Liu

et al. 2019

J Virol

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“…3a). The HPV16 oncoprotein E7 disrupts the p53-DREAM repressor complex, thereby resulting in the upregulation of several cell cycle-related genes and abrogation of p53-mediated cell cycle control (27,28). For the common genes, protein interaction For microarray analysis of each tissue type, three primary cell lines and three HPV16-transformed cell lines were used to grow rafts.…”

Section: Resultsmentioning

confidence: 99%

Tissue-Specific Gene Expression during Productive Human Papillomavirus 16 Infection of Cervical, Foreskin, and Tonsil Epithelium

Chatterjee

Kang

Alam

et al. 2019

J Virol

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Epidemiological data confirm a much higher incidence of high-risk human papillomavirus 16 (HPV16)-mediated carcinogenesis of the cervical epithelium than for other target sites. In order to elucidate tissue-specific responses to virus infection, we compared gene expression changes induced by productive HPV16 infection of cervical, foreskin, and tonsil organotypic rafts. These rafts closely mimic persistent HPV16 infection, long before carcinogenesis sets in. The total number of gene expression changes varied considerably across the tissue types, with only 32 genes being regulated in common. Among them, we confirmed the Kelch-like family protein KLHL35 and the laminin-5 complex to be upregulated and downregulated, respectively, in all the three tissues. HPV16 infection induces upregulation of genes involved in cell cycle control, cell division, mitosis, DNA replication, and DNA damage repair in all the three tissues, indicative of a hyperproliferative environment. In the cervical and tonsil epithelium, we observe significant downregulation of genes involved in epidermis development, keratinocyte differentiation, and extracellular matrix organization. On the other hand, in HPV16-positive foreskin (HPV16 foreskin) tissue, several genes involved in interferon-mediated innate immunity, cytokine signaling, and cellular defenses were downregulated. Furthermore, pathway analysis and experimental validations identified important cellular pathways like STAT1 and transforming growth factor β (TGF-β) to be differentially regulated among the three tissue types. The differential modulation of important cellular pathways like TGF-β1 and STAT1 can explain the sensitivity of tissues to HPV cancer progression. IMPORTANCE Although the high-risk human papillomavirus 16 infects anogenital and oropharyngeal sites, the cervical epithelium has a unique vulnerability to progression of cancer. Host responses during persistent infection and preneoplastic stages can shape the outcome of cancer progression in a tissue-dependent manner. Our study for the first time reports differential regulation of critical cellular functions and signaling pathways during productive HPV16 infection of cervical, foreskin, and tonsil tissues. While the virus induces hyperproliferation in infected cells, it downregulates epithelial differentiation, epidermal development, and innate immune responses, according to the tissue type. Modulation of these biological functions can determine virus fitness and pathogenesis and illuminate key cellular mechanisms that the virus employs to establish persistence and finally initiate disease progression.

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“…Since MYBL2 itself is a DREAM target gene, this might create a positive feedback loop in which B-Myb overexpression drives further B-Myb expression and perpetuates DREAM disruption. 46 This is also relevant to HPV-positive cancers with E7-mediated DREAM complex disassembly. [46][47][48][49][50] Indeed, T98G cells expressing viral oncoproteins have higher amounts of B-Myb and MMB as compared to cells with intact DREAM.…”

Section: Discussionmentioning

confidence: 99%

“…46 This is also relevant to HPV-positive cancers with E7-mediated DREAM complex disassembly. [46][47][48][49][50] Indeed, T98G cells expressing viral oncoproteins have higher amounts of B-Myb and MMB as compared to cells with intact DREAM. 51,52 B-Myb was also identified as a target for E7-mediated transcriptional activation, leading to inappropriate expression of B-Myb in G1 and higher steady state levels in cycling cells, mimicking our model of B-Myb overexpression.…”

Section: Discussionmentioning

confidence: 99%

The cell cycle gene regulatory DREAM complex is disrupted by high expression of oncogenic B-Myb

Iness

Felthousen

Ananthapadmanabhan

et al. 2017

Preprint

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The oncogene MYBL2 (encoding B-Myb) is a poor prognostic biomarker in many cancers. B-Myb interacts with the MuvB core of five proteins (LIN9, LIN37, LIN52, LIN53/RBBP4, and LIN54) to form the MMB (Myb-MuvB) complex and promotes expression of late cell cycle genes necessary for progression through mitosis. Both MYBL2 amplification and over-expression are associated with deregulation of the cell cycle and increased cell proliferation. Alternatively, by interacting with E2F4-DP1 and p130 or p107, the MuvB core becomes part of the DREAM complex (DP, RB-like, E2F, and MuvB). The DREAM complex opposes MMB by globally repressing cell cycle genes in G0/G1, maintaining the cell in a quiescent state. However, the specific mechanism by which B-Myb alters the cell cycle is not well understood. Our analysis of The Cancer Genome Atlas data revealed significant upregulation of DREAM and MMB target genes in breast and ovarian cancer with MYBL2 gain. Given that most of the DREAM target genes are not directly regulated by B-Myb, we investigated the effects of B-Myb on DREAM formation. We found that depletion of B-Myb results in increased DREAM formation in human cancer cells, while its overexpression inhibits DREAM formation in the non-transformed cells. Since the MuvB core subunit LIN52 is essential for assembly of both the DREAM and MMB complexes, we tested whether B-Myb disrupts DREAM by sequestering LIN52. Overexpression of LIN52 did not increase either DREAM or MMB formation, but instead increased the turnover rate of the endogenous LIN52 protein. Interestingly, co-expression of B-Myb increased the expression of both endogenous and overexpressed LIN52 while knockdown of B-Myb had an opposite effect. We found that regulation of LIN52 occurs at the protein level, and that activity of DYRK1A kinase, the enzyme that triggers DREAM complex formation by phosphorylating LIN52, is required for this regulation. These findings are the first to implicate B-Myb in the disassembly of the DREAM complex and offer insight into the underlying mechanisms of poor prognostic value of MYBL2 amplification in cancer. We conclude that B-Myb mediates its oncogenic effects not only by increasing mitotic gene expression by the MMB complex, but also by broad disruption of cell cycle gene regulatory programs through compromised DREAM formation.

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

Cited by 80 publications

References 61 publications

Human Papillomavirus E6/E7 and Long Noncoding RNA TMPOP2 Mutually Upregulated Gene Expression in Cervical Cancer Cells

Human Papillomavirus E6/E7 and Long Noncoding RNA TMPOP2 Mutually Upregulated Gene Expression in Cervical Cancer Cells

Tissue-Specific Gene Expression during Productive Human Papillomavirus 16 Infection of Cervical, Foreskin, and Tonsil Epithelium

The cell cycle gene regulatory DREAM complex is disrupted by high expression of oncogenic B-Myb

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