Main Body
Chapter 5: Mis regulated Gene expression in disease
Mis regulated Gene expression in disease
Dr.V.Malathi
Learning Objectives
By the end of this chapter, readers will be able to:
- Discuss the importance of gene expression regulation
- Explain the link between dysregulated gene expression and cancer
- Discuss the role of dysregulated gene expression in auto immune diseases
Altered Gene Expression and Cancer
Altered gene expression or dysregulated gene expression plays a role in the development of disease like Cancer. Proteins are turned on or expressed by gene activation and are turned off by gene silencing. This gene expression regulation determines the overall activity of the cell. A gene that is not normally expressed in a cell can be switched on and expressed at high levels due to gene mutation or changes in gene regulation ( epigenetic, transcription, post-transcription, translation, or post-translation).Changes at each of these levels can be detected in different types of cancer in different individuals. Scientific studies had reported changes in histone acetylation , activation of transcription factors by phosphorylation, increased RNA stability, increased translational control, and protein modification etc., to be involved in the development of various cancers.
These are genes active in normal cells that function to prevent uncontrolled cellular proliferations example, p53 gene .This gene is mutated in over 50 percent of all cancer types. The p53 protein itself functions as a transcription factor and can bind to promoters of genes to initiate transcription. Therefore, the mutation of p53 in cancer alter the transcriptional activity of its target genes.
Proto-Oncogenes
which are positive cell-cycle regulators. When mutated, proto-oncogenes can become oncogenes and cause cancer..
When their expression is deregulated in cancers there can be overexpression and can become the oncogene leading to uncontrolled cell growth. For example the Myc protein ,which is a transcription factor .Aberrantly activated Myc results in a cancer of the lymph system called Overexpression of myc transforms normal B cells into cancerous cells that continue to grow uncontrollably and develop as tumors of the jaw or mouth that interfere with the ability to eat.
Epigenetic Alterations
Silencing genes through epigenetic mechanisms is also very common in cancer cells. Certain histone and DNA modifications are associated with silenced genes. The DNA in the promoter region of silenced genes is methylated on cytosine DNA residues in CpG islands in most cancer cells.
Altered Transcription control
Mutations may activate transcription factors and can increase the binding of a transcription factor to a promoter. This could lead to increased transcriptional activation of that gene. This in turn results in modified cell growth and proliferation. Also mutations in promoter or enhancer region can increase the binding ability of a transcription factor. This could also lead to the increased transcription and aberrant gene expression that is seen in cancer cells. For example Breast cancer cells over express the epidermal growth factor receptor (EGFR). The EGFR pathway activates many protein kinases that, in turn, activate many transcription factors that control genes involved in cell growth. Therefore drugs that prevent the activation of EGFR have been developed to treat breast cancer .
Altered expression of miRNAs
miRNAs bind to the 3′ UTR of RNA molecules and degrade them. Overexpression of these miRNAs could be detrimental to normal cellular activity. Increased expression of miRNAs could decrease the RNA population and in turn decrease protein expression. Several studies have demonstrated change in the miRNA population in specific cancer types. Aberrantly expressed miRNAs is also reported contributing to the pathogenesis of multiple sclerosis
Altered Post translational control
Increased translation of a protein, changes in protein phosphorylation , variants of alternative splicing are found in cancer cells. For example ,the c-Flip protein , a protein involved in mediating the cell death pathway, exists in two forms: long (c-FLIPL) and short (c-FLIPS). In normal cells both the isoforms appear to be involved in initiating controlled cell death mechanisms . However, in colon cancer cells, long form is seen to over expressed . This results in increased cell growth instead of cell death.
Genes in normal cells that function to prevent uncontrolled cell divisions
Genes when mutated that can become Oncogenes and cause cancer
Cancer of the lymph system caused due to aberrant expression of Myc protein