The paper appeared in the Science Express category, which is the editors-in-chief’s selection of the best works published in the Science magazine.
The paper entitled “PML regulates apoptosis at endoplasmic reticulum by modulating calcium release” is a result of cooperation between scientists from Poland, Italy and the United States. Its Polish authors are Prof. Jerzy Duszyński, Dr. Hab. Mariusz Więckowski and PhD candidate Magda Lebiedzińska from the Nencki Institute of Experimental Biology, Polish Academy of Sciences.
Researchers have demonstrated that disturbances in communication between intracellular structures can lead to formation of cancer lesions. Their truly innovative discovery is that one of the important links of this communication is the PML protein (promyelocytic leukaemia protein), a suppressor of promyelocytic leukaemia – a malignant tumour of the blood and bone marrow.
As has been known already for years, genetic damage of the PML protein is at the base of many neoplastic diseases. The cell’s genetic material is vulnerable to damage resulting from exposure to various environmental factors, such as harmful chemical compounds or ionizing radiation. Normal PML protein, located in the cell’s nucleus is needed to identify this damage. Therefore, when PML abnormal variant is formed, DNA damage could accumulate in the cells and in consequence lead to development of tumour lesions.
However the PML protein is located not only in the cell’s nucleus, but also in other cellular compartments. To date the role of the extranuclear PML protein was poorly understood. The paper published in the latest issue of the Science magazine, delivered in cooperation with scientists from Harvard University and University of Ferrara, explains this issue in depth.
The study, described in the paper, employed the newest techniques of molecular biology and cutting age laboratory equipment to show that the PML protein is an important participant in the process of the programmed cell death (apoptosis) and explain the mechanism of its involvement in this process.
Apoptosis is a phenomenon whereby millions of cells in our organism are undergoing self-destruction every minute. For example many “unwanted” cells in the blood are continuously being replaced with new cells. Should these „unwanted” cells disintegrate in an uncontrolled way, we would have to deal with permanent and acute inflammation. In the process of apoptosis, on the other hand, cells disintegrate into tiny vesicles, which are absorbed by specialized cells. There is no inflammation and in addition many components of the unwanted cells are „recycled” within the organism.
Body cells with damaged genetic material or cells infected with a virus also die the apoptic death. Cancer cells, however, are quite resistant to apoptosis. It is actually believed that disturbed apoptosis could lead to formation and development of cancer. If we were able to overcome the resistance of cancer cells to enter apoptosis, we could significantly limit the development of neoplastic disease.
In their work published in Science, the Polish-Italian-American research team demonstrated that within the cell the PML protein is located also in the contact zone of mitochondria and the endoplasmic reticulum where signal transduction using calcium ions takes place. Scientists have demonstrated that the correct from of PML is needed to generate this signal (other proteins participating in this communication have also been identified). Mitochondria activated with the calcium signal initiate the process of apoptosis in the cell.
This provides an accurate and full explanation of the mechanism of PML protein’s essential involvement in the proper execution of the process of apoptosis. Scientists have shown why cells with abnormal PML protein not only accumulate damage to the genetic material but also are resistant to the programmed cell death.
Results of this work indicate that the PML protein could constitute a target of a new anti-tumour therapy.
Based on a Polish Press Agency release of November 23, 2010.
*Giorgi C, Ito K, Lin HK, Santangelo C, Wieckowski MR, Lebiedzinska M, Bononi A, Bonora M, Duszynski J, Bernardi R, Rizzuto R, Tacchetti C, Pinton P, Pandolfi PP. (2010) PML Regulates Apoptosis at Endoplasmic Reticulum Modulating Calcium Release. Science 330: 1247-51.