Researchers have found an unexpected link between a gene that enables stem cells to keep renewing themselves - Sox2 - and a previously unrelated gene called p27, which is involved in many types of human cancer.
The findings increase understanding of stem cells and have implications for research into diseases linked to the loss of either gene.
The work was carried out by Robin Lovell-Badge of the MRC's National Institute for Medical Research (now part of the Francis Crick Institute) in collaboration with Manuel Serrano and colleagues at the Instituto de Investigaciones Sanitarias in Spain and the Spanish National Cancer Research Centre.
Stem cells are immature cells that have not yet developed into the specialised cells that make up our organs and tissues. Depending on their origin and type, they are able to generate different types of cell, such as blood cells or nerve cells. Stem cells also have the ability to "self-renew", or make identical copies of themselves, almost indefinitely. They have the potential to be used to treat many human diseases.
There are two broad types of stem cell - embryonic stem cells, which come from a very early stage embryo and therefore have the abilty to make all cell types of the body - and adult stem cells, which are found in many tissues throughout the body and throughout a person's lifetime, where their role is to replace cells specific to that tissue that are lost through normal processes of wear and tear. A third type, called induced pluripotent stem cells, can be produced by forcing an adult cell, even a specialised one like a skin cell, to express certain genes that cause them to be re-programmed into cells with the characteristics of embryonic stem cells.
The Sox2 gene produces a protein that is essential for maintaining self-renewal of many types of stem cell, including both embryonic stem cells and adult, tissue-specific, stem cells. It is part of a family of proteins that play key roles in many stages of development in mammals.
Conversely, the p27 gene encodes a protein that is responsible for stopping or slowly down the cell division cycle. This process goes awry in many cancers; in fact, low levels of p27 protein indicate a poor prognosis for several types of cancer. Furthermore, heritable mutations in the p27 gene are responsible for a group of human tumour disorders.
The researchers studied mice that were missing the p27 gene and found raised levels of Sox2 protein, indicating that p27 plays a role in repressing the Sox2 gene when it's not needed. Skin cells lacking p27 were able to be reprogrammed into induced pluripotent stem cells even without adding Sox2, which is usually one of the essential reprogramming factors.
Mice lacking p27 have increased body size, enlarged organs, tumours in their pituitary glands and an eye disorder called retinal dysplasia. But when these mice also have only one (rather than two) active copies of Sox2, many of these problems were corrected. For example, in the pituitary, stem cell proliferation reverted back to roughly normal levels and tumours were no longer so prevalent.
Dr Lovell-Badge said: "This study is important because it shows links between Sox2 and p27. But what makes it particularly novel is that p27 acts directly to regulate Sox2 expression - which is a surprise.
"Our results are relevant for studying the ability of stem cells to form almost any cell type, and for generating induced pluripotent cells - which bypass the need to use embryonic stem cells. The findings also have implications for the disorders that occur when one or other gene is lost in a number of tissues - and human diseases related to this."
The article, P27Kip1 directly contributes to Sox2 transcriptional repression during embryonic stem cell differentiation, is published in Cell Stem Cell.
