Cell Signalling How Signal Errors and Mutations can

Cell Signalling How Signal Errors and Mutations can cause Cancer

Signalling Proteins • A cell must be able to respond to changes in their environment by receiving and processing signals from outside the cell. • Cells often receive many messages simultaneously but can integrate them into a unified single action in the cell. • All cell signals act as ligands that bind to a receptor but there are considerable differences in structure and function of molecules that act as signals e. g. A single Gas to a Complex Protein. • Some signals travel throughout an organism while others act locally on adjoining cells. • Signals can bind to extracellular receptors to trigger an intracellular secondary messenger while some can pass through the cell membrane to bind with intracellular receptors or on the nucleus membrane itself. • With such a complex series of pathways in an organism or cell there are many opportunities for errors or mutations in a cells life cycle.

The Cell Cycle • The cell cycle is controlled by a series of complex metabolic signals in a molecular pathway. • This is how a cell grows, replicates its DNA and divides. • These processes contain mechanisms to ensure cellular errors are not replicated. • If these mechanisms fail under normal circumstances a cell commits Apoptosis which is a programmed cell death. • If Apoptosis malfunctions due to a cellular mutation the cell may proliferate uncontrollably causing Tumours or Cancer.

Programmed Cell Death (PCD) • PCD is a regulated process that is advantageous to an organism i. e. In human embryos PCD occurs between finger and toe cells to allow the digits to separate. • Apoptosis and Autophagy are examples of PCD and are a fundamental part of a multicellular organisms life cycle. • PCD stops errors and mutations from being expressed.

Cancer Causing Genes • • • Oncogenes An Oncogene is a gene that has the potential to cause Cancer. In Tumour cells they are often mutated or expressed in high levels. An activated/mutated Oncogene may cause other cells designated for Apoptosis to survive and proliferate They generally need an additional step such as a mutation or a viral infection to cause Cancer. Proto-Oncogenes A normal gene that may become an Oncogene due to mutation or excessive expression. These code for proteins that regulate cell growth and cell differentiation. They are involved in signal Transduction and the execution of mitogenic signals through their protein products. Upon activation they become an Oncogene which is a tumour/cancer inducing agent. Examples of Proto-Oncogenes are; RAS, WNT, MYC, ERK, TRK, MYC, JUN, FOS.

Growth Factor Receptors (GFR) • GFR are the cell-surface receptors for the epidermal growth factor family of extracellular protein ligands. • Somatic mutations involving epidermal GFR leads to its constant activation, which produces uncontrolled cell division and may result in cancer. • Overexpression of epidermal GFR has been associated with several cancers including: squamous-cell carcinoma of the lung (80% of cases), glioblastoma (50%) and epithelial tumours of the head and neck (80 -100%).

Proto-oncogene Tyrosine Kinase (src) • C-SRC is a non-receptor tyrosine kinases protein encoded by the SRC gene. • The protein phosphorylates specific tyrosine residues. • An elevated level of C-SRC tyrosine kinase is associated with cancer progression by promoting other signals.

RAS • RAS is a family of proteins that are expressed in all animal cell lineages and organs. • They a small GTPase involved in signal transduction pathways. RAF is a protein found downstream from RAS, mutated RAF genes have been found in many cancers. ) • When RAS is “switched on” it activates other proteins (e. g. RAF), which ultimately turn on genes involved in cell growth, differentiation and survival. • When mutations occur that permanently activate RAS without any incoming signal it causes uncontrolled cell growth, which ultimately leads to cancer. • This is one of the most common oncogenes in human cancer, with 20 -25% of all human tumours and up to 90% of certain types of cancer (e. g. pancreatic) have been found to be linked to overactivation of RAS gene.

MYC • MYC is a regulatory gene that codes for a transcription factor. • The protein encoded by the gene is a multifunctional, nuclear phosphoprotein involved in the cell cycle progression, apoptosis and cellular transformation. • When a mutation occurs that causes MYC to be permantly active it leads to uncontrolled expression of many genes, some of which are involved in cell proliferation, resulting in many types of cancer. • Malfunctions in MYC are involved in: development of Burkitt lymphoma, carcinoma of the cervix, colon, breast, lung, and stomach.

JUN and FOS • C-JUN and C-FOS are proteins that from the heterodimer AP-1 that is a transcriptional factor, involved in gene expression and cell growth. • It is activated through double phosphorylation by the JNK pathway. • AP-1 interacts directly with DNA at specific target sequences to regulate gene expression. • Mutations in FOS and JUN genes cause uncontrolled gene expression. • JUN and FOS play an important role in many cellular functions, and have been found overexpressed in several cancers.