Mechanisms of p53 restriction in Merkel cell carcinoma cells are independent of the Merkel cell polyoma virus T antigens.

Abstract

Merkel cell carcinoma (MCC) is a rare and very aggressive skin cancer with viral etiology. The tumor-associated Merkel cell polyoma virus (MCV) belongs to a group of viruses encoding T antigens (TAs) that can induce tumorigenesis by interfering with cellular tumor-suppressor proteins like p53. To explore possible modes of p53 inactivation in MCC p53 sequencing, expression analysis and reporter gene assays for functional analyses were performed in a set of MCC lines. In one MCV-negative and one MCV-positive cell line, p53 inactivating mutations were found. In the majority of MCC lines, however, wild-type p53 is expressed and displays some transcriptional activity, which is yet not sufficient to effectively restrict cellular survival or growth in these cell cultures. Interestingly, the MCV TAs are not responsible for this critical lack in p53 activity, as TA knockdown in MCV-positive MCC cells does not induce p53 activity. In contrast, inhibition of the ubiquitin ligase HDM-2 (human double minute 2) by Nutlin-3a leads to p53 activation and p53-dependent apoptosis or cell cycle arrest in five out of seven p53 wild-type MCC lines, highlighting p53 as a potential target for future therapies of this aggressive tumor.

• Authors: Roland Houben, Christina Dreher, Sabrina Angermeyer, Andreas Borst, Jochen Utikal, Sebastian Haferkamp, Wiebke K Peitsch, David Schrama, Sonja Hesbacher
• Journal: The Journal of investigative dermatology (J Invest Dermatol) Vol. 133 Issue 10 Pg. 2453-2460 (Oct 2013) ISSN: 1523-1747 [Electronic] United States
• PMID: 23563200 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, Viral, Tumor
• TP53 protein, human
• Tumor Suppressor Protein p53
• MDM2 protein, human
• Proto-Oncogene Proteins c-mdm2

Topics

• Antigens, Viral, Tumor (genetics)
• Carcinoma, Merkel Cell (genetics, pathology, virology)
• Cell Line, Tumor
• Gene Expression Regulation, Neoplastic
• Gene Expression Regulation, Viral
• Genes, Reporter
• Humans
• Merkel cell polyomavirus (genetics)
• Polyomavirus Infections (genetics, pathology)
• Proto-Oncogene Proteins c-mdm2 (antagonists & inhibitors, metabolism)
• Signal Transduction (genetics)
• Skin Neoplasms (genetics, pathology, virology)
• Transcriptional Activation (genetics)
• Tumor Suppressor Protein p53 (genetics)
• Tumor Virus Infections (genetics, pathology)