Why are signal transduction pathways seen as so attractive for pharmacological and therapeutic intervention? The first reason is because the whole of biology and physiology is controlled by a network of biochemical interconnections, globally referred to as signal transduction. Signal transduction proteins control cell fate, for example, regulating decisions to proliferate, differentiate, or undergo apoptosis (Fig. 4). Malfunction of signal transduction processes caused by mutation or abnormal gene expression leads to incorrect decisions being made about cell fate and function, resulting in disease. Abnormal signaling can bring about hyperproliferative disorders, such as cancer, atherosclerosis, restinosis, and psoriasis, and also inflammatory diseases, such as rheumatoid arthritis (52,53).
In cancer, oncogenes and tumor suppressor genes are positioned at critical points on signal transduction pathways, or oncoprotein networks, that control cell fate (54). Mutation or abnormal expression of genes involving signal transduction proteins leads to neoplastic transformation and malignant progression.
Figure 5 shows a very simplified view of the signal transduction pathways leading from receptor tyrosine kinases located at the cell membrane and connecting with the cell-cycle machinery and the control of gene expression in the nucleus. Cancer cells activate these pathways by, for example, overexpression of receptors, such as epidermal growth factor (EGF) receptor and erbB2; mutational activation of the Ras oncogene; biochemical activation of the Src tyrosine kinase; deregulation of the transcription factor Myc; and various alterations in the cyclins, cyclin-dependent kinases, their regulatory proteins, or loss of the retinoblastoma gene product (12,55).
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