Abstract
p53 is a well-known tumor suppressor gene and one of the most extensively studied genes in cancer research. p53 functions largely as a transcription factor and can trigger a variety of antiproliferative programs via induction of its target genes. We identified PHLDA3 as a p53 target gene and found that its protein product is a suppressor of pancreatic neuroendocrine tumors (PanNETs) and a repressor of Akt function. PHLDA3 is frequently inactivated by loss of heterozygosity (LOH) and methylation in human PanNETs, and LOH at the PHLDA3 gene locus correlates with PanNET progression and poor prognosis. In addition, in PHLDA3-deficient mice, pancreatic islet cells proliferate abnormally and acquire resistance to apoptosis. In this article, we briefly review the roles of p53 and Akt in human neuroendocrine tumors (NETs) and describe the relationship between the p53-PHLDA3 and Akt pathways. We also discuss the role of PHLDA3 as a tumor suppressor in various NETs and speculate on the possibility that loss of PHLDA3 function may be a useful prognostic marker for NET patients indicating particular drug therapies. These results suggest that targeting the downstream PHLDA3-Akt pathway might provide new therapies to treat NETs.
Highlights
Abstract: p53 is a well-known tumor suppressor gene and one of the most extensively studied genes in cancer research. p53 functions largely as a transcription factor and can trigger a variety of antiproliferative programs via induction of its target genes
We observed a significantly high frequency of loss of heterozygosity (LOH) at both the PHLDA3 and MEN1 loci. These results suggest that the functional loss of both the PHLDA3 and MEN1 genes is necessary for the development of human pancreatic neuroendocrine tumors (PanNETs) and inactivation of these pathways cooperatively contribute to PanNET development (Figure 2D) [14]
We have shown that the PHLDA3 gene is a p53 target gene and encodes a repressor of Akt
Summary
P53 is a well-known tumor suppressor gene that is mutated in more than half of human cancers of various types and contributes to their development [1,2,3,4]. p53 is a transcription factor that induces its target genes in accordance with the type and intensity of cell damage. P53 is a well-known tumor suppressor gene normally present in all human cells that is usually activated by various types of stress, such as DNA damage, hypoxia, or oncogene activation [15,16,17,18,19,20,21,22]. In response to these signals, p53 undergoes various post-translational modifications including phosphorylation and acetylation and both its expression levels and subcellular localization are altered. These results identified PHLDA3 as a p53 target gene
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