Oncogenes PDF

Oncogenes Dr.Haroon Habib Ala too international University  INTRODUCTION Oncogenes are mutated or overexpressed versions of normal cellular genes, known as proto-oncogenes, which regulate essential cellular processes like growth, proliferation, and survival. Under...

Oncogenes Dr.Haroon Habib Ala too international University  INTRODUCTION Oncogenes are mutated or overexpressed versions of normal cellular genes, known as proto-oncogenes, which regulate essential cellular processes like growth, proliferation, and survival. Under normal circumstances, proto-oncogenes help control cell division and differentiation, ensuring that cells grow and respond appropriately to external signals. This led to the discovery that similar genes exist in human cells and can be activated through mutations. The activation of oncogenes is one of the fundamental steps in the development of cancer, as these altered genes drive the continuous growth and division of cells, bypassing normal regulatory mechanisms.  Types and origins of oncogenes Proto-oncogenes become oncogenes through various processes, each resulting in excessive activity that can disrupt normal cell function: Point mutations (a single DNA change) may permanently activate the gene's protein product. Gene amplification increases the number of gene copies, leading to an overproduction of proteins that stimulate cell diffusion. Chromosomal translocations (a reorganization of DNA) can result in a new, fusion gene with abnormal function. Examples of well-known oncogenes include RAS, MYC, and HER2/ neu. Each of these genes plays a different role in cell growth and regulation, and understanding them provides insights into how their normal functions can go awry.  Functions of Oncogene The action of growth factors as oncogene proteins results from their abnormal expression, leading to a situation in which a tumor cell produces a growth factor to which it also responds. The result is autocrine stimulation of the growth factor-producing cell , which drives abnormal cell proliferation and contributes to the development of a wide variety of human tumors. A large group of oncogenes encode growth factor receptors, most of which are protein-tyrosine kinases. These receptors are frequently converted to oncogene proteins by alterations of their amino-terminal domains, which would normally bind extracellular growth factors.  For example, the receptor for platelet-derived growth factor (PDGF) is converted to an oncogene in some human leukemia's by a chromosome translocation in which the normal amino terminus of the PDGF receptor is replaced by the amino terminal sequences of a transcription factor called Tel. The Tel sequences of the resulting Tel/PDGFR fusion protein dimerize in the absence of growth factor binding, resulting in constitutive activity of the intracellular kinase domain and unregulated production of a proliferative signal from the oncogene protein. Alternatively, genes that encode some receptor protein-tyrosine kinases, such as erbB-2, are activated by gene amplification. Other oncogenes (including src and abl) encode nonreceptor protein-tyrosine kinases that are constitutively activated by deletions or mutations of regulatory sequences.  FUNCTIONS The Ras proteins play a key role in mitogenic signaling by coupling growth factor receptors to activation of the Raf protein-serine/threonine kinase, which initiates a protein kinase cascade leading to activation of the ERK MAP kinase. The raf gene can similarly be converted to an oncogene by deletions that result in loss of the amino-terminal regulatory domain of the Raf protein. These deletions result in unregulated activity of the Raf protein kinase, which also leads to constitutive MAP kinase activation. The MAP kinase pathway ultimately leads to the phosphorylation of transcription factors and alterations in gene expression. As might therefore be expected, many oncogenes encode transcriptional regulatory proteins that are normally induced in response to growth factor stimulation.  For example, transcription of the fos proto-oncogene is induced as a result of phosphorylation of Elk-1 by the ERK MAP kinase. Fos and the product of another proto-oncogene, Jun, are components of the AP-1 transcription factor, which activates transcription of a number of target genes in growth factor-stimulated cells. Constitutive activity of AP-1, resulting from unregulated expression of either the Fos or Jun oncogene proteins, is sufficient to drive abnormal cell proliferation, leading to cell transformation. The Myc proteins similarly function as transcription factors regulated by mitogenic stimuli, and abnormal expression of myc oncogenes contributes to the development of a variety of human tumors. Other transcription factors are frequently activated as oncogenes by chromosome translocations in human leukemias and lymphomas.  Mechanism The activation of oncogenes involves genetic changes to cellular protooncogenes. The consequence of these genetic alterations is to confer a growth advantage to the cell. Three genetic mechanisms activate oncogenes in human neoplasms: (1) mutation, (2) gene amplification, and (3) chromosome rearrangements. These mechanisms result in either an alteration of protooncogene structure or an increase in protooncogene expression Because neoplasia is a multistep process, more than one of these mechanisms often contribute to the genesis of human tumors by altering a number of cancer-associated genes. Full expression of the neoplastic phenotype, including the capacity for metastasis, usually involves a combination of protooncogene activation and tumor suppressor gene loss or inactivation.  MUTATION :Mutations activate protooncogenes through structural alterations in their encoded proteins. These alterations, which usually involve critical protein regulatory regions, often lead to the uncontrolled, continuous activity of the mutated protein. Various types of mutations, such as base substitutions, deletions, and insertions, are capable of activating protooncogenes. Retroviral oncogenes, for example, often have deletions that contribute to their activation. Examples include deletions in the aminoterminal ligand-binding domains of the erb B, kit, ros, met, and trk oncogenes.In human tumors, however, most characterized oncogene mutations are base substitutions (point mutations) that change a single amino acid within the protein.  Gene Amplification Gene amplification refers to the expansion in copy number of a gene within the genome of a cell. Gene amplification was first discovered as a mechanism by which some tumor cell lines can acquire resistance to growth-inhibiting drugs. The process of gene amplification occurs through redundant replication of genomic DNA, often giving rise to karyotypic abnormalities called double-minute chromosomes (DMs) and homogeneous staining regions (HSRs). DMs are characteristic minichromosome structures without centromeres. HSRs are segments of chromosomes that lack the normal alternating pattern of light- and dark-staining bands. Both DMs and HSRs represent large regions of amplified genomic DNA containing up to several hundred copies of a gene. Amplification leads to the increased expression of genes, which in turn can confer a selective advantage for cell growth.  Significance in Cancer Development Oncogenes are central to understanding how cancer develops and progresses. For instance: Tumor formation: Oncogenes can initiate tumor growth by promoting excessive cell division. Metastasis: Some oncogenes affect cellular adhesion and movement, allowing cancer cells to spread to other parts of the body. Angiogenesis: Oncogenes can promote blood vessel formation to sustain tumors by supplying nutrients and oxygen. Genomic instability: Certain oncogenes increase the likelihood of additional mutations, leading to further genetic chaos in cancer cells.  One of the fundamental features of cancer is tumor clonality, the development of tumors from single cells that begin to proliferate abnormally. The single-cell origin of many tumors has been demonstrated by analysis of X chromosome inactivation. One member of the X chromosome pair is inactivated by being converted to heterochromatin in female cells. X inactivation occurs randomly during embryonic development, so one X chromosome is inactivated in some cells, while the other X chromosome is inactivated in other cells. Thus, if a female is heterozygous for an X chromosome gene, different alleles will be expressed in different cells. Normal tissues are composed of mixtures of cells with different inactive X chromosomes, so expression of both alleles is detected in normal tissues of heterozygous females. In contrast, tumor tissues generally express only one allele of a heterozygous X chromosome gene. The implication is that all of the cells constituting such a tumor were derived from a single cell of origin, in which the pattern of X inactivation was fixed before the tumor began to develop. Significance in Cancer Development  Clinical Implications The study of oncogenes has significantly advanced cancer diagnosis and treatment: Diagnostic markers: Some oncogenes, like HER2, are used as markers to diagnose specific cancers or determine prognosis. Targeted therapies: Understanding oncogenes has enabled the development of treatments tailored to specific cancers. For example, drugs like trastuzumab target the HER2 gene in breast cancer, and imatinib targets the BCR-ABL fusion protein in chronic myeloid leukemia (CML). Challenges: Despite these advances, cancers can develop resistance to these treatments, indicating the need for combination therapies and further research.  Conclusion Oncogenes play a vital role in the field of cancer biology by helping us understand the molecular mechanisms driving cancer. The ongoing study of oncogenes is not only key to developing more effective treatments but also to identifying new ways to diagnose cancer early. As research progresses, new therapeutic targets may emerge, providing hope for more personalized cancer treatments in the future.