Defining the role of kindlin-1 in the regulation of microtubule stability and mitosis (Brunton 1)Completed
|Project lead||Prof Valerie Brunton|
|Organisation||The University of Edinburgh, Edinburgh Cancer Research Centre, Institute of Genetics and Molecular Medicine, Edinburgh, UK|
|Project budget||GBP 191,838.00|
|Start date / Duration||01. Sep 2014 / 37 months|
|Funder(s) / Co-Funder(s)||DEBRA UK, MSAP/EBEP Recommended|
|Research area||EB genetics, epigenetics & biology|
Short lay summary
Kindler syndrome (KS), named after the doctor who first described it, is a type of Epidermolysis Bullosa (EB) in which the skin is fragile, sensitive to light and blisters in response to trauma. As the person ages, their skin becomes thin, making it vulnerable to damage. Patients with KS are also more susceptible to developing a type of skin cancer called squamous cell carcinoma. KS is caused by inheriting a fault in a gene called KIND1 (or FERMT1) which normally controls production of a protein: Kindlin-1.This particular protein is important in the processes of cell division (known as mitosis) and growth in skin cells. The faulty gene will produce a Kindlin-1 protein that does not function properly, contributing to the thin and fragile skin. However, the way in which Kindlin-1 contributes to these processes at the molecular level is not yet fully understood.
Aims of the Research
It is understood that Kindlin-1 is an ‘adaptor’ protein, which means that it functions by binding to other proteins in the cell. This project wanted to understand how Kindlin-1 interacts with other proteins involved in cell division. The group has techniques available in their laboratory that has enabled them to identify which proteins interact with each other and also where inside the cell the interactions take place.
Normal skin cells were compared with those from people with KS to gain insight into the steps in cell division that are not functioning properly in KS skin. Work to increase our understanding of how Kindlin-1 functions contributes to our ability to devise ways in which we can treat this disease.
“Our research has identified how Kindlin-1 controls important processes in cells that allow them to grow and also protect themselves from UV damage. We now need to understand how we can restore these processes in people with KS to provide much needed treatments.”
What did this project achieve?
Initial observations showed that lack of Kindlin-1 reduced the number of cells that are able to go through cell division (mitosis) and thus, multiply, which could account for the thin (atrophic) skin seen in KS patients. Further investigation into the process of cell division revealed that Kindlin-1 controls microtubule stability. Microtubules are involved in maintaining the structure of the cell and are the major component of the mitotic “spindle” and are needed to separate chromosomes during mitosis which allows the cells to divide successfully and correctly. The mitotic spindle had a higher chance of being mis-oriented and unstable in cells lacking Kindlin-1. Kindlin-1 is important as it helps to provide stability by binding to microtubules, critical to maintaining the structure of the cell and cell division. In KS where a patients’ skin does not have any Kindlin-1, there is reduced cell division, fewer cells which we now know can result in thin or atrophic skin.
To better understand what other proteins Kindlin-1 binds to during cell division; the team have carried out a comprehensive analysis. Having identified binding partners of Kindlin-1, they have established that Kindlin-1 binds to a key regulator of cell cycle progression called CDK. CDK controls the transit of cells through the cell cycle which is the process whereby cells divide.
They also found that cells from the skin of patients with KS are more sensitive to Ultra Violet (UV) damage. UV irradiation (sunlight) causes damage to DNA and leads to cells dying and Kindlin-1 is able to protect cells from this damage. KS patients have increased photosensitivity which means that they are more sensitive to UV light. It is thought that Kindlin-1 protects skin from UV damage by activating survival pathways in cells. These survival pathways are a linked series of proteins within cells and their activity sends survival signals to the cells. The team have identified one such protein called ERK that is involved in this survival pathway where the activity is regulated by Kindlin-1.
Conclusion of this research
Whilst the team has learned more about the cellular processes involved in KS, they now need to establish whether, and how, some of these proteins or markers impact the fragility of KS skin. The team hopes that by identifying proteins or markers supporting cellular stability or survival, this might allow us to identify targets for treatment in the future.
Kindlin-1 associates with microtubules at the mitotic spindle - Courtesy of Professor Brunton