Oncogenes

An oncogene is a gene that has the potential to cause cancer. In tumor cells, they are mutated or expressed at high levels. Most normal cells undergo a programmed form of rapid cell death (apoptosis) when critical functions are altered.

1. ONCOGENES - Vishakha Upadhyay

2. Oncogenes produce proteins that have the capacity to stimulate growth and proliferation . Oncogenes are derived from proto oncogenes which are genes that encode proteins having function in normal cells They are dominant or “gain of function” mutations . They may lead to genetic instability, preventing a cell from becoming a victim of apoptosis or promote metastasis Different oncogenes become activated in different types of tumors, which reflects variations in the signaling pathways that operate in diverse cell types. Oncogenes

3. The activity of the normal protein is regulated by another tyrosine kinase that phosphorylates src at T-527 (p-527 src is inactive). v- src has a deletion in 18 aa at the C-T that includes T-527. Therefore , v- src or appropriate cellular mutants (c- src ) have constitutive tyrosine kinase activity, therefore unregulated cell growth and proliferation. All oncogenes have been found in normal cell equivalent genes/proteins and are termed “proto-oncogenes”. First discovered through the ability of Rous sarcoma virus (RSV) to cause cancer in chickens. Mutant studies of RSV: the src gene causes cancer! Transfection of cells with src or other oncogenes. e.g., ras or jun leads to neoplastic transformation. “There is a normal cell equivalent of this so-called “oncogene” and it codes for a protein that has been associated with tyrosine kinase activity, that stimulated growth and proliferation via protein phosphorylation in signal transduction pathways”. Discovery of oncogenes

4. Growth factors – rare but an example is sis which codes for a mutant PDGF (platelet derived growth factor) aberrantly auto stimulates proliferation of cells containing PDGF receptors. Sis is present in cancer causing Simian Sarcoma Virus Cultured cells transformed with this virus secretes large amount of PDGF into medium, which causes cells to proliferate in uncontrolled fashion Growth factor receptors - Oncogenes encoding cell surface receptors that transduce growth promoting signals have been associated with several types of cancer. e.g., erb b is a mutant form of epidermal growth factor receptor. This receptor functions as a tyrosine protein kinase (CT of protein) located on the cytoplamic side of the membrane with the ligand binding region (NT of protein) facing the cell exterior . In erb b the receptor protein is missing the N-terminal ligand binding domain on the cell surface exterior and the C-terminal tyrosine protein kinase is in a permanently turned on state. Oncoproteins

5. A point mutation changes a normal RTK into one that dimerizes and is constitutively activated even in the absence of ligand A single point mutation converts the normal Her2 receptor into new oncoprotein - Neuroblastoma

6. Intracellular transducers e.g., ras (a mutant form of an inner cell surface GTPase ) , whose function activates a number of other regulatory factors including another oncogene termed raf (a protein kinase) that work in concert to regulate cell proliferation via the MAP Kinase Pathway which activates transcription factors proto-oncogene = ras Oncogene = mutated ras Always activated Always stimulating proliferation

7. amino acid position Ras gene 12 59 61 Tumor c-ras (H, K, N) Gly Ala Gln normal cells H-ras Gly Ala Leu lung carcinoma Val Ala Gln bladder carcinoma K-ras Cys Ala Gln lung carcinoma Arg Ala Gln lung carcinoma Val Ala Gln colon carcinoma N-ras Gly Ala Lys neuroblastoma Gly Ala Arg lung carcinoma Murine sarcoma virus H-ras Arg Thr Gln Harvey strain K-ras Ser Thr Gln Kirsten strain Amino acid substitutions in Ras family proteins (inactivates GTPase )

8. Nuclear transcription factors like myc. The myc protein is a key factor involved in activation of gene transcription in cells going from a non –proliferating state. Stimulates transcription of genes that promote progression through G1 phase of cell cycle and G1 to S transition If myc gene expression is blocked using anti-sense oligonucleotides , cell cycle progression is stopped. Over expression of c- myc is characteristic of many cancers. Conversion of c Myc proto oncogene can occur via different mechanisms such as translocation under constitutive active promoter Oncogenes that encode products that affect Apoptosis Apoptosis is process of distruction of cancerous cells. Inability to carry on apoptosis can result in tumor e.g., Bcl2 proto oncogene

9. Activation mechanisms of proto-oncogenes proto-oncogene --> oncogene

10. Hyperactivation of Myc

11. CHROMOSOMAL REARRANGEMENTS OR TRANSLOCATIONS Neoplasm Translocation Proto-oncogene Burkitt lymphoma t(8;14) 80% of cases c-myc 1 t(8;22) 15% of cases t(2;8) 5% of cases Chronic myelogenous t(9;22) 90-95% of cases bcr-abl 2 leukemia Acute lymphocytic t(9;22) 10-15% of cases bcr-abl 2 Leukemia 1 c-myc is translocated to the IgG locus, which results in its activated expression 2 bcr-abl fusion protein is produced, which results in a constitutively active abl kinase

12. GENE AMPLIFICATION Oncogene Amplification Source of tumor c- myc ~20-fold leukemia and lung carcinoma N- myc 5-1,000-fold neuroblastoma retinoblastoma L- myc 10-20-fold small-cell lung cancer c- abl ~5-fold chronic myoloid leukemia c- myb 5-10-fold acute myeloid leukemia colon carcinoma c- erbB ~30-fold epidermoid carcinoma K- ras 4-20-fold colon carcinoma 30-60-fold adrenocortical carcinoma

13. Oncogenic retroviruses • Cancer is a genetic disease- oncogenesis consists of the processes that result in growth of cells in which mutations have accumulated • Viruses are a contributing factor in about 20% of all human cancers • Growth properties and morphologies of cultured cells could be changed upon infection with certain viruses- cells become transformed • Cells become immortal in an early step in oncogenesis-they continue to grow and divide even though the body has sufficient numbers of these cells They lose contact inhibition and the need to adhere to a surface They look different, more rounded

14. • Oncogenesis is the result of genetic changes that alter the expression or function of proteins that play critical roles in the control of cell growth and division • Oncogenic viruses cause cancer by inducing changes that affect cell growth and division • Cancer arises from a combination of dominant gain of function mutations in proto- oncogenes and recessive loss of function mutations in tumor suppressor genes Oncogenic viruses

15. • Oncogenic viruses were discovered by Ellerman and Bang in 1908 who showed that avian leukemia can be transmitted by filtered extracts of leukemic cells • In 1911 Peyton Rous showed that solid tumors can be produced in chicken using cell free extracts

16. Oncogenic retroviruses are classified into two groups: 1) Transducing oncogenic retroviruses: - highly carcinogenic, cause malignancies in 100% of the infected animals in a matter of days - cause cancer because their genomes contain transduced cellular genes that become oncogenes -virally transduced versions of cellular genes are called v- oncogenes , their cellular counterparts are called c- oncogenes or proto- oncogenes 2) Nontransducing oncogenic retroviruses: -less carcinogenic -do not encode cell derived oncogenes -activate transcription of proto- oncogenes by integration of the provirus close to these genes in the host genome Additional mutations are required - common

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