Research projects

This 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.