Funded Grants

Cellular transformation by c-FOS: A nuclear and cytoplasmic event?

Cancer is a predominant disease of our time which drives a wide spectrum of research. Among the different types of cancer, brain tumors are not the most common. However, they are particularly frightening: they often affect children and young people, and they rapidly impair vital and mental functions, leading to death. Also, treatment of brain tumors offers few effective alternatives compared to other cancer types.

Tumor formation is a multi-step process that reflects dynamic and complex changes occuring in the genome of a cell, where all the genes containing a complete set of inheritable information is stored. These changes in the genome result from mutations that progressively drive the transformation of normal cells into malignant derivatives. Cancer cells are defined by two heritable properties: they divide in defiance of the normal control restraints and they invade and colonize the territory reserved for other cells. In spite of the complexity of cancer, there is an underlying principal in all cancer cells: uncontrolled, malignant growth.

The accumulation of particular proteins, because they are over-expressed or because they are not normally degraded, is sufficient for cell transformation. Although these proteins are constituents of normal cells, they receive the name of proto-oncoproteins because of their transforming capacity when unregulated. One of these proto-oncoproteins is c-Fos. It has been postulated that c-Fos forms a complex with another proto-oncoprotein, c-Jun, and is imported into the nucleus where it binds to DNA and regulates the expression of target genes important for cell growth. We recently described that, in addition to its capacity to regulate the expression of target genes, c-Fos is capable of regulating the synthesis of a family of lipids called phospholipids (Bussolino et al. 2001, FASEB J. published online). These lipids are the quantitatively most important components of all cell membranes. Large scale biosynthesis of phospholipids is required for the generation of new membrane necessary for proliferation of tumor cells. To our knowledge, we identified the only protein - c-Fos - known up to date that is capable of activating the enzyme machinery responsible for phospholipid synthesis.

We are directing our research efforts towards understanding how cells manage to create enough new membrane to support normal and exaggerated growth. In this project, we propose to examine the participation of c-Fos and other proto-oncoproteins in regulating phospholipid synthesis to support membrane genesis required for cell growth, in normal and transformed cells of the nervous system. It is expected that the comprehension of these cellular functions will enable researchers to intervene in these processes and control malignant cell growth.

The specific aim of this proposal is to study the molecular mechanism by which c-Fos activates phospholipid synthesis to support growth in normal and transformed neural cells. For this, we will take advantage of the possibility of using normal and transformed cell lines in culture systems. These cell lines are homogenous populations of cells that have been immortalised. That is, they will proliferate indefinitely and their progeny will have the same characteristics as the mother cells. We have used neural cells in culture and have found that their growth rate strictly correlates with their content in c-Fos and with their synthesis of phospholipids: if c-Fos expression Is blocked once the nuclear program for growth and differentiation has been triggered, cells stop synthesizing phospholipids rapidly and growth goes to a halt. If, on the contrary, we increase cellular c-Fos content by specifically impairing its degradation, this protein accumulation stimulates the rats of synthesis of phospholipids. As a result, cells grow more and faster than those in which c-Fos is normally eliminated by degradation.

At this stage of our research, we consider it very important to define precisely the molecular mechanism by which c-Fos stimulates phospholipid synthesis and consequently cell growth. Preliminary results to our lab indicate that in order to activate phospholipid biosynthesis, c-Fos interacts with other cellular proteins that catalyze the set of reactions responsible for the synthesis of these lipids. If we establish these interactions, then new strategies to curb the spread of cancer can be approached. For example, we can design drugs targeted to interfere with these interactions so that phospholipid synthesis is reduced, in an attempt to control the uncontrolled growth that is the hallmark of all forms of cancer. Such strategies aimed at restricting brain tumor formation while leaving other functions of Fos unaffected are very rare and very valuable. More importantly, they would bring hope to both physicians and patients.