Abstract
p53 is a central tumor suppressor protein and its inhibition is believed to be a prerequisite for cancer development. In approximately 50% of all malignancies this is achieved by inactivating mutations in the p53 gene. However, in several cancer entities, including melanoma, p53 mutations are rare. It has been recently proposed that tyrosinase related protein 2 (TRP2), a protein involved in melanin synthesis, may act as suppressor of the p53 pathway in melanoma. To scrutinize this notion we analyzed p53 and TRP2 expression by immunohistochemistry in 172 melanoma tissues and did not find any correlation. Furthermore, we applied three different TRP2 shRNAs to five melanoma cell lines and could not observe a target specific effect of the TRP2 knockdown on either p53 expression nor p53 reporter gene activity. Likewise, ectopic expression of TRP2 in a TRP2 negative melanoma cell line had no impact on p53 expression. In conclusion our data suggest that p53 repression critically controlled by TRP2 is not a general event in melanoma.
Highlights
Advanced melanoma is a cancer that is largely resistant to cytotoxic drugs or irradiation; this had been at least in part attributed to an impaired p53 dependent apoptosis response [1]
tyrosine-related protein 2 (TRP2) acts in the melanin synthesis pathway downstream of tyrosinase catalysing the conversion of dopachrome to 5,5dihydroxyindole-2-carboxylic acid (DHICA) [16,17,18]
On the other hand of all 120 samples with middle to strong TRP2 staining 44 (37%) displayed very weak or negative p53 staining. Taken together these analyses reveal, that p53 expression is independent of the TRP2 expression level
Summary
Advanced melanoma is a cancer that is largely resistant to cytotoxic drugs or irradiation; this had been at least in part attributed to an impaired p53 dependent apoptosis response [1]. The transcriptional activity of p53 can be impaired on a posttranslational level by competition for DNA-binding sites by the p73 isoform DNp73 [6,7], functional antagonism with the inhibitor of apoptosis-stimulating protein (iASPP) [6,8] and sequestration in the cytosol by the ubiquitin ligase Parc [9]. All of the aforementioned p53 inactivation mechanisms except inhibition by viral oncoproteins have been described in melanoma cells. This is of particular interest since p53 is frequently expressed in melanoma but inactivating mutations are rarely detectable [11,12,13,14]. TRP2 knockdown in WM266-4 melanoma cells lead to increased p53 expression sensitizing the cells to cisplatin-induced apoptosis
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