It is determined that the p73 gene is involved in the formation of tumour vasculature
Cristina G. Pedraz/DICYT Researchers of the Cell Differentiation and Models Group of the Biomedicine Institute of the University of León (Instituto de Biomedicina de la Universidad de León, Ibiomed), in collaboration with the groups of Dr Lena Claesson-Wells of the University of Uppsala in Sweden and Dr Kanaga Sabapathy of the National Cancer Centre of Singapore, have shown that the p73 gene is necessary for the formation of blood vessels both when new (vasculogenesis) and from the vascular bed (angiogenesis).
Both studies published in the journals Cell Death & Differentiation and Nature Cell Biology, which is one of the most important journals in the world in the field of cell biology, have confirmed that the lack of p73 affects the capacity of the formation and organisation of the vasculature of both healthy individuals and tumours.
“This capacity of tumour cells to induce the vascularisation of the tumour is essential to the tumour's development and its capacity of invasion and metastasis. The various forms of the p73 protein (isoforms) operate in a contrasting manner in the regulation of this function, which means that the regulation of the expression of this gene is an important factor in tumour progression; this makes p73 an interesting therapeutic target for cancer treatment”, indicate Carmen Marín and Margarita Marqués, the co-authors of both studies and co-directors of the Cell Differentiation and Models Group of the Ibiomed.
Four research groups from various parts of the world, including that of León, have shown at the same time that this gene has a very important function in the progression of the tumour as it is involved in the formation of the vasculature. These groups are those directed by Gerry Melino of Leicester University in the United Kingdom; by Dr Margareta T. Wilhelma, of the Karolinska Institutet in Sweden; and by Dr Kanaga Sabapathy of the National Cancer Centre of Singapore.
A controversial gene
The Ibiomed Group divides its scientific and research activities into two interconnected branches. Part of their efforts are concentrated on basic science, on the study of the function of the tumour suppressor genes p73 and p53. Likewise, the use of the models generated during these studies can extend to the study of other genes and they may be used to search for compounds of pharmacological interest.
In basic research the Group is working to identify the function of p73 and p53 in cell reprogramming, in the process of neurogenesis, and in the processes of vasculogenesis and angiogenesis. In these cases the research is aimed at the functional study of the members of the gene family of the p53 tumour suppressor gene, both in physiological processes during development and in the pathology of various diseases such as cancer or neurodegenerative disorders.
“The p73 gene is very similar to the p53 tumour suppressor gene. However, while the function of p53 in the establishment and progression of cancer in humans has been widely studied, the role of p73 has been highly controversial”, explains Dr Carmen Marín, the main researcher of the group.
P53 acts as a barrier to the establishment and progression of the tumour. “The p53 gene is mutated or inactive in most tumours in humans and is known as the “watchdog” of the human genome, as when it is active it responds to the detection of damage to the genome, inducing its repair or preventing this damage or mutation from passing to the next cell generation”, she adds. For this reason, the function of p53 is crucial in the response to chemotherapeutical treatment and the development of resistance.
On the other hand, the reason why it has been more difficult to identify the function of the p73 is because this gene gives rise to more than one type of proteins or isoforms, in some cases with conflicting functions. As a result, “the regulation of the differential expression of p73 is very important and decisive in its function”, the researchers point out.
Future steps
The forthcoming objectives of the research group are the analysing of the regulation of p73 in the response to hypoxia (the lack of oxygen) in systems such as the maintenance of the neurogenic niches of the brain, which is highly relevant in neurodegenerative diseases. It also plans to use these models to identify compounds capable of regulating the differential expression of p73.
The Cell Differentiation and Models Group of the Ibiomed is formed by Drs Carmen Marín and Margarita Marqués, in addition to two pre-doctoral researchers under contract (Marta Martín-López and Sandra Fuertes-Álvarez) and a master's degree student (Laura Maeso Alonso), all of whom are biotechnologists. This study was initiated by Dr Rosalía Fernández-Alonso as part of her doctoral thesis and continued and completed by the graduate Marta Martín-López, who is the co-author of both articles. The Group also includes the doctors of the Complejo Hospitalario de León Alfonso Fernández-Corona and Elena Lorenzo, who are co-authors of this study together with the doctor of the University of León Inmaculada Diez-Prieto.
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Bibliographical references: |
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Dulloo, I., Phang, B. H., Othman, R., Tan, S. Y., Vijayaraghavan, A., Goh, L. K., Martín López, M., Marqués, M. M., Wei Li, C., Wang, D. Y., Marín, M. C., Xian, W.,Mckeon, F. y Sabapathy, K. (2015). “Hypoxia-inducible TAp73 supports tumorigenesis by regulating the angiogenic transcriptome”. Nature cell biology. doi:10.1038/ncb3130.
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