Integration of the HPV16 genome does not invariably result in high levels of viral oncogene transcripts

BACKGROUND Companion biomarkers are biomarkers that are used in combination with specific therapies and that prospectively help predict likely response or severe toxicity. In this article we review the role of companion biomarkers in guiding treatment in patients with cancer. CONTENT In addition to the established companion biomarkers such as estrogen receptors and HER2 (human epidermal growth factor receptor 2) in breast cancer, several new companion biomarkers have become available in recent years. These include v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations for the selection of patients with advanced colorectal cancer who are unlikely to benefit from anti–epidermal growth factor receptor antibodies (cetuximab or panitumumab), epidermal growth factor receptor (EGFR) mutations for selecting patients with advanced non–small cell lung cancer (NSCLC) for treatment with tyrosine kinase inhibitors (gefitinib or erlotinib), v-raf murine sarcoma viral oncogene homolog B1 (BRAF) mutations for selecting patients with advanced melanoma for treatment with anti-BRAF agents (vemurafenib and dabrafenib), and anaplastic lymphoma receptor tyrosine kinase (ALK) translocations for identifying patients with NSCLC likely to benefit from crizotinib. SUMMARY The availability of companion biomarkers should improve drug efficacy, decrease toxicity, and lead to a more individualized approach to cancer treatment.

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Tumor Suppressor p53 Stimulates the Expression of Epstein-Barr Virus Latent Membrane Protein 1

Journal of Virology ◽

10.1128/jvi.00312-17 ◽

2017 ◽

Vol 91 (20) ◽

Cited By ~ 6

Author(s):

Qianli Wang ◽

Amy Lingel ◽

Vicki Geiser ◽

Zachary Kwapnoski ◽

Luwen Zhang

Keyword(s):

Dna Damage ◽

Tumor Suppressor ◽

Epstein Barr Virus ◽

Latent Membrane Protein ◽

Latent Membrane Protein 1 ◽

Tumor Suppressor P53 ◽

Viral Oncogene ◽

Barr Virus ◽

Lmp1 Expression ◽

Epstein Barr

ABSTRACT Epstein-Barr virus (EBV) is associated with multiple human malignancies. EBV latent membrane protein 1 (LMP1) is required for the efficient transformation of primary B lymphocytes in vitro and possibly in vivo. The tumor suppressor p53 plays a seminal role in cancer development. In some EBV-associated cancers, p53 tends to be wild type and overly expressed; however, the effects of p53 on LMP1 expression is not clear. We find LMP1 expression to be associated with p53 expression in EBV-transformed cells under physiological and DNA damaging conditions. DNA damage stimulates LMP1 expression, and p53 is required for the stimulation. Ectopic p53 stimulates endogenous LMP1 expression. Moreover, endogenous LMP1 blocks DNA damage-mediated apoptosis. Regarding the mechanism of p53-mediated LMP1 expression, we find that interferon regulatory factor 5 (IRF5), a direct target of p53, is associated with both p53 and LMP1. IRF5 binds to and activates a LMP1 promoter reporter construct. Ectopic IRF5 increases the expression of LMP1, while knockdown of IRF5 leads to reduction of LMP1. Furthermore, LMP1 blocks IRF5-mediated apoptosis in EBV-infected cells. All of the data suggest that cellular p53 stimulates viral LMP1 expression, and IRF5 may be one of the factors for p53-mediated LMP1 stimulation. LMP1 may subsequently block DNA damage- and IRF5-mediated apoptosis for the benefits of EBV. The mutual regulation between p53 and LMP1 may play an important role in EBV infection and latency and its related cancers. IMPORTANCE The tumor suppressor p53 is a critical cellular protein in response to various stresses and dictates cells for various responses, including apoptosis. This work suggests that an Epstein-Bar virus (EBV) principal viral oncogene is activated by cellular p53. The viral oncogene blocks p53-mediated adverse effects during viral infection and transformation. Therefore, the induction of the viral oncogene by p53 provides a means for the virus to cope with infection and DNA damage-mediated cellular stresses. This seems to be the first report that p53 activates a viral oncogene; therefore, the discovery would be interesting to a broad readership from the fields of oncology to virology.

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Human c-fms proto-oncogene: comparative analysis with an abnormal allele

Molecular and Cellular Biology ◽

10.1128/mcb.5.2.422-426.1985 ◽

1985 ◽

Vol 5 (2) ◽

pp. 422-426

Author(s):

J S Verbeek ◽

A J Roebroek ◽

A M van den Ouweland ◽

H P Bloemers ◽

W J Van de Ven

Keyword(s):

Comparative Analysis ◽

Dna Sequencing ◽

Sequencing Analysis ◽

Base Pairs ◽

Small Deletion ◽

Viral Oncogene ◽

Close Proximity ◽

Genetic Sequences ◽

Dna Sequencing Analysis

The organization of the human c-fms proto-oncogene has been determined and compared with an abnormal allele. The human v-fms homologous genetic sequences are dispersed discontinuously and colinearly with the viral oncogene over a DNA region of ca. 32 kilobase pairs. The abnormal c-fms locus contains a small deletion in its 3' portion. DNA sequencing analysis indicated that it was 426 base pairs in size and located in close proximity to a putative c-fms exon.

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