Necdin, a p53-target gene, is an inhibitor of p53-mediated growth arrest.

Abstract

In vitro, cellular immortalization and transformation define a model for multistep carcinogenesis and current ongoing challenges include the identification of specific molecular events associated with steps along this oncogenic pathway. Here, using NIH3T3 cells, we identified transcriptionally related events associated with the expression of Polyomavirus Large-T antigen (PyLT), a potent viral oncogene. We propose that a subset of these alterations in gene expression may be related to the early events that contribute to carcinogenesis. The proposed tumor suppressor Necdin, known to be regulated by p53, was within a group of genes that was consistently upregulated in the presence of PyLT. While Necdin is induced following p53 activation with different genotoxic stresses, Necdin induction by PyLT did not involve p53 activation or the Rb-binding site of PyLT. Necdin depletion by shRNA conferred a proliferative advantage to NIH3T3 and PyLT-expressing NIH3T3 (NIHLT) cells. In contrast, our results demonstrate that although overexpression of Necdin induced a growth arrest in NIH3T3 and NIHLT cells, a growing population rapidly emerged from these arrested cells. This population no longer showed significant proliferation defects despite high Necdin expression. Moreover, we established that Necdin is a negative regulator of p53-mediated growth arrest induced by nutlin-3, suggesting that Necdin upregulation could contribute to the bypass of a p53-response in p53 wild type tumors. To support this, we characterized Necdin expression in low malignant potential ovarian cancer (LMP) where p53 mutations rarely occur. Elevated levels of Necdin expression were observed in LMP when compared to aggressive serous ovarian cancers. We propose that in some contexts, the constitutive expression of Necdin could contribute to cancer promotion by delaying appropriate p53 responses and potentially promote genomic instability.

• Authors: Julie Lafontaine, Francis Rodier, Véronique Ouellet, Anne-Marie Mes-Masson
• Journal: PloS one (PLoS One) Vol. 7 Issue 2 Pg. e31916 ( 2012) ISSN: 1932-6203 [Electronic] United States
• PMID: 22355404 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, Polyomavirus Transforming
• Biomarkers
• Nerve Tissue Proteins
• Nuclear Proteins
• RNA, Messenger
• Tumor Suppressor Protein p53
• necdin

Topics

• Animals
• Antigens, Polyomavirus Transforming (genetics, metabolism)
• Apoptosis
• Biomarkers (metabolism)
• Blotting, Northern
• Blotting, Western
• Cell Cycle
• Cell Proliferation
• Cell Transformation, Neoplastic (pathology)
• Cells, Cultured
• Cystadenocarcinoma, Serous (genetics, metabolism)
• Female
• Fibroblasts (cytology, metabolism)
• Flow Cytometry
• Gene Expression Profiling
• Humans
• Immunoenzyme Techniques
• Mice
• NIH 3T3 Cells
• Nerve Tissue Proteins (genetics, metabolism)
• Nuclear Proteins (genetics, metabolism)
• Oligonucleotide Array Sequence Analysis
• Ovarian Neoplasms (genetics, metabolism)
• RNA, Messenger (genetics)
• Real-Time Polymerase Chain Reaction
• Tumor Suppressor Protein p53 (genetics, metabolism)