Signal Transduction
Receptor Transcription Factors
Some transmembrane receptors, upon activation, become transcription factors that transcribe sets of genes essential for cellular processes such as growth, differentiation (changes in structure and/or function), apoptosis (programmed cell death), and homeostasis (maintenance of the cell's internal equilibrium). Carcinogenesis often begins with receptors being aberrantly activated, leading to increased expression of genes involved in these cellular processes.
Introduction
Cells respond to their environment through a ‘ligand’, for example, a hormone, growth factor or cytokine, binding to, and activating, receptors. Receptors can be localized on the cell’s surface or inside the cell, e.g. in the nucleus. One of the first steps during carcinogenesis is the hijacking of the cell’s regulatory signals, which is frequently achieved by the inappropriate activation of a receptor. This inappropriate activation, either by genetic alterations that cause constitutive activation, or receptor ‘over-expression’ resulting in many more copies than usual being present, deregulate the controls that govern normal cellular processes.
Some transmembrane and nuclear receptors are involved in the direct transcription of target genes. The transcription function of the receptor is often activated by a structural modification, or proteolytic processing that produces functional protein fragments. The activated protein dimerizes with another receptor/receptor fragment prior to, or after, being translocated into the nucleus. Some receptor dimers act directly as a transcription factor, and some act as a co-factor that assists the binding of the transcription factor to the gene’s promoter sequence. The ‘messenger RNA’ (mRNA) products of these target genes are then ‘translated’ into functional proteins. It is through this mechanism of ligand-induced gene expression by the receptor, that the cell is able to initiate cellular processes appropriate for its environment.
LICR investigators are studying several key receptor transcription factors in order to understand their roles in normal cell function, and how these roles are disrupted in cancer. Importantly, the LICR teams are also investigating whether these receptor transcription factors might also represent new targets for cancer therapies.
- Nurr Family - the Nurr family of nuclear receptors is critical for cell growth and apoptosis, and its members are constitutively activated in many cell types. LICR scientists have shown that the Nurr1 receptor is essential for the development of the midbrain dopamine cells that degenerate in Parkinson’s disease, and may be critical in other neurological disorders. Nurr1 has become a prime target for the development of drugs for both cancer and/or neurological conditions.
- Notch Family - the Notch family of transmembrane receptors is crucial for stem cell maintenance, and cell differentiation during fetal and postnatal development. Amplified Notch signaling, via the overexpression of Notch ligands or the constitutive activation of the receptors, has been shown to result in the development of cancers (leukemias and lymphomas) derived from the T cells of the human immune system.
Patient Oriented Research
Nurr1, and other NRs studied by LICR scientists, are critical in regulating cell growth, apoptosis and differentiation. An important goal at LICR is to test if agonists and antagonists of Nurr1 can be of benefit for patients with cancer and other disorders such as Parkinson’s disease.