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Projects. Life and Earth Sciences

In vivo nuclear reprogramming and the functional interrelationship between p27 and SOX2

Lead Researcher:
Manuel Serrano Marugán

Research Centre:
Centro Nacional de Investigaciones Oncológicas, Madrid.

Synopsis:

Manuel Serrano MarugánThis project is divided into two subprojects respectively entitled "Nuclear reprogramming in the normal context of an organism (in vivo)" (subproject 1) and "The functional interrelationship between tumour suppressor p27 and the Sox2 transcription factor" (subproject 2). The CNIO Tumour Suppression Group has recently created "reprogrammable mice", in which the simple administration of a compound triggers a genetic switch in all the cells in the animal model and expresses the so-called four factors of nuclear reprogramming (4F). This tool makes it possible for the first time to study the capacity of the 4F to induce the expansion of the progenitor compartments within the context of the organism and to collect data that may be useful as a test of the principle for future regenerative therapies. It is also proposed to undertake mechanistic studies of the relationship between p27 tumour suppressor and the Sox2 pluripotency gene. These studies as a whole may aid comprehension of the relationship between cancer and pluripotency, making it possible to understand the working of in vivo cell regeneration.

  • The objectives of subproject 1:
    • Reprogramming and tissue regeneration.
    • Ageing and reprogramming.
    • Reprogramming and cancer.
  • The objectives of subproject 2:
    • Elucidation of the role of p27 in the reprogramming of induced pluripotent stem cells (iPS).
    • Elucidation of the molecular mechanisms connecting p27 and Sox2.
    • Determination of the in vivo functional interrelationship between p27 and Sox2.

Results

An unprecedented mechanistic connection which is relevant for cancer has been found between the p27 tumour suppressor and the Sox2 transcription factor. p27 binds and represses the expression of Sox2.

The clue to connecting p27 and Sox2 was discovered when studying the reprogramming of cells that lack the p27 gene, when it was observed that iPS cells can be reprogrammed without the need for ectopic expression of Sox2. This led to the study of whether there is a link between two previously unrelated proteins: p27 and Sox2. It was shown that p27 contributes to the transcriptional repression of Sox2. The absence of p27 leads to a defective repression of Sox2 in different types of tissues, together with an incomplete and retarded silencing of Sox2 during the differentiation of pluripotent cells. In the absence of p27, pituitary tissue expresses high levels of Sox2, and this is the basis for the development of pituitary tumours. p27 was characterised as a new transcriptional regulator of p27 together with a repressive complex composed of p130, E2F4 and SIN3A in a critical amplifier responsible for the expression of Sox2.

Scientific production
9 articles published in Journals

 

Researcher's web address:

 http://www.cnio.es/es/grupos/plantillas/presentacion.asp?grupo=50004260 



Manuel Serrano Marugán

Since 2003, Manuel Serrano has been head of the Tumoral Suppression Group in the National Cancer Research Centre (Madrid), where, since 2012, he has also been director of the Molecular Oncology Programme.

Manuel Serrano has made major scientific contributions in the field of Oncology. By May, 2012, he had contributed a total of 158 scientific articles which have accumulated a total of 15,905 citations, together with three international and operational patents. His h index stands at 49. The following of his contributions have had special repercussion:

  • The discovery, cloning and characterisation of the p16 tumour suppressor, which defined a new type of cell cycle regulators.
  • The establishment for the first time of the concept of "oncogene induced senescence" as a tumoral suppression mechanism.
  • The first in vivo identification of senescent tumoral cells.
  • The first generation of cancer-resistant mice, the so-called "super-mice", which have increased resistance against cancer without harmful side effects.
  • The identification of tumoral suppressors p53 and P16/ARF as one of the main barriers against the cellular reprogramming of adult cells into induced pluripotent stem cells (iPS).
  • The discovery that the tumoral suppressor Pten also fights obesity, thereby establishing a direct link between metabolism and cancer.


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