Interactions Between Metallothionein and p53: Potential Role in Tumorgenesis

The p53 tumor suppressor protein is an important regulator of cell cycle progression and apoptosis. Phosphorylation and acetylation modify p53 resulting in increased p53 levels and stability in response to stress. The activated p53 promotes transcription of various target genes involved in cell proliferation and apoptosis. Loss of p53 activity disrupts cell homeostasis and induces chromosomal abnormalities. Mutations of p53 occur in more than half of all human tumors and are associated with unfavorable prognosis of survival for patients.

Metallothionein (MT) is involved in the homeostasis of essential metals due to its metal-binding properties. MT is involved in the regulation of cell proliferation and apoptosis, and protects both cells from metal-induced stress and free radicals. Most vertebrate tissues express low levels of MT. Over-expression of MT has been reported in human tumors including breast cancer, ovarian cancer, renal cell carcinoma, and pancreatic carcinoma.

In our research we have shown that p53 plays a crucial role in the transcriptional regulation of MT, which indicates a novel regulatory role for p53. Active p53 is required for metal induced MRE and MTF-1-mediated activation of MT transcription whereas the high basal level of MT in the absence of active p53 is MRE, AP1, and MTF1 independent.

On the other hand, our research has also shown that the semi metal-free apo-form of MT interacts with p53 in the cell suggesting that it may prevent binding of p53 to DNA. This may result in an inability of p53 to act as a transcriptional factor. Thus, over-expression of MT may lead to inactivation of p53 and MT may therefore be involved as a control mechanism to regulate p53 activity.

Our present research is aimed at determining the inter-play between MT and p53. We are interested in identifying the mechanism leading to up-regulation of MT in cells with reduced p53 activity. The goal is to develop novel treatment strategies that involve the reduction of MT levels in tumors.

Activities

1. Identification of factors affecting MT regulation in p53 positive and negative cells.
2. Determination of the interaction between MT and p53.

Relevant publications

Kling P, Modig C, Mujahed H, Khalaf H, von Hofsten J, Olsson PE. 2013. Differential regulation of the rainbow trout (Oncorhynchus mykiss) MT-A gene by nuclear factor interleukin-6 and activator protein-1. BMC Mol Biol. 14:28

Ostrakhovitch, E.A., Olsson, P.-E., von Hofsten, J. and Cherian, G. (2007) p53 mediated regulation of metallothionein transcription. J. Cell. Biochem. 102, 1571-1583.

Ostrakhovitch, E.A., Olsson, P.-E., Jiang, S. and Cherian, C. (2006) Interaction of metallothionein with tumor suppressor p53 protein. FEBS letters 580, 1235-1238.

Kling, P. and Olsson, P.-E. (2005) Metallothionein structure and regulation. In: Biochemistry and Molecular Biology of Fishes. Vol. 6. Environmental Toxicology. T.P. Mommsen & T.W. Moon (eds.) pp 289-302.

Kling, P. and Olsson, P.-E. (2000) Involvement of differential metallothionein expression in free radical sensitivity of RTG-2 and CHSE-214 cells. Free Rad. Biol. Med. 28(11) 1628-1637.