Oncogenes and Tumor Suppressors
Cancer is a complex disease involving abnormal cell growth due to genetic mutations in oncogenes and tumor suppressor genes. Oncogenes promote cell proliferation, while tumor suppressors inhibit cancer development by regulating cell death, repair, and differentiation.
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Presentation Transcript
P.G. ONCOGENES AND CANCER VBC-608 1.12.2020
CANCER The term cancer applies to a group of diseases in which cells grow abnormally & form malignant tumor. Malignant cells can invade nearby tissues and metastasize. This aberrant growth pattern results from mutations in genes that regulate proliferation, differentiation, and survival of cells in a multicellular organism. Because of these genetic changes, cancer cells no longer respond to the signals that govern growth of normal cells. Activation of oncogenes or absence /inactivation of tumor suppressor genes can lead to cancer.
NORMAL CELLS VS. CANCER CELLS Cancer cells- Lose control over the growth and multiplication. Do not self destruct when they become worn out or damaged. Crowd out healthy cells
DEFINITIONS Oncogenes- The genes involved in the development of cancer. Normal cells do contain DNA sequence similar to viral oncognenes. To distinguish these two genes: V-src (viral gene) and C-src (cellular gene). Protooncogenes- Normal constituents of cells whose function is to promote proliferation or cell survival. These genes can code for growth factors, growth factor receptors, signal transduction proteins, intracellular kinases and transcription factors. Tumor suppressor genes(normal growth suppressor genes)- Encode proteins that encode proliferation, promote cell death or repair DNA
PROTOONCOGENES Protooncogenes are regulatory genes. Products of many protooncogenes are polypeptide growth factors. e.g.- sis gene produce PDGF- normal wound healing. Product act as receptor for growth factor. e.g.- erb-B produces receptor for EGF. Protooncogenes are under the control of regulatory genes and expressed only when required. When virus enters, an extra oncogene is inserted so as to produce continuous expression of gene leading to uncontrolled cellular activity & malignant transformation.
PROTO-ONCOGENE TO ONCOGENE An alteration occurs in a normal cellular gene (proto-oncogene) that makes the protein hyper- functional (oncogene) Proteins involved in the cell signaling pathways are products of proto-oncogenes Proliferative Anti-apoptotic (survival) Angiogenic
TUMOR SUPPRESSORS Normally function to suppress the formation of cancer Growth arrest Apoptosis DNA repair Differentiation Anti-angiogenesis
Tumor suppressors are recessive require mutation of both alleles Oncogenes are dominant mutation of 1 allele is sufficient
COMPARISON OF PROTO-ONCOGENES AND TUMOR SUPPRESSORS Property Tumor suppressor genes Proto-oncogenes Alleles mutated in cancer Both alleles One allele Germ line transmission of mutant allele frequent Rare (1 example) Somatic mutations yes yes Loss of function (recessive allele) Gain of function (dominant allele) Function of mutant allele Effects on cell growth Inhibit cell growth Promote cell growth
FACTORS AFFECTING PROTOONCOGENES Tumor Virus Chemical carcinogens Chromosomal translocation Radiations Spontaneous mutation All such factors may converge into one biochemical abnormalities Activation of protooncogenes leading to malignancy 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 inactivation of tumor suppressor gene
ONCOGENES BY FUNCTION Growth factors Growth factor receptors G proteins Intracellular kinases Transcription factors
MECHANISMS OF ACTIVATION 5 mechanisms of activation- Promoter insertion Enhancer insertion Chromosomal translocation Gene amplification Point mutations
PROMOTER INSERTION Certain retroviruses lack oncogenes(e.g.- avian leukemia viruses)but may cause cancer over a long period of time. In retrovirus, cDNA is made from their RNA by reverse transcriptase. cDNA gets inserted into host genome. Integrated dscDNA provirus This proviral DNA takes control over the transcription of cellular chromosomal DNA & transforms the cell. e.g.- Avian Leukemia
ENHANCER INSERTION Avian leukemia virus integration and acts as enhancer of myc gene Normal Chicken Chromosome (inactive myc gene)
CHROMOSOMAL TRANSLOCATION Rearrangement of genetic material by splitting off a small fragment of chromosome which is joined to another chromosome. Over expression of proto oncogenes eg: Burkitts lymphoma Chronic myeloid leukemia
ALTERS STRUCTURE OF NORMAL c-abl PROTEIN The bcr/abl fusion, created on the chromosome 22, encodes a chimeric protein of 210 kDa, with increased tyrosine kinase activity and abnormal cellular localization. 20% of cases of ALL Overexpression of the bcl-2 protein inhibits apoptosis, leading to an imbalance between lymphocyte proliferation and programmed cell death
ALTERED c-myc c-myc finds itself in a region of active gene transcription, and it may simply be the overproduction of the c-myc product (a transcription factor essential for cell division) that propels the lymphocyte down the pathway towards cancer.
