Cancer &Oncogenes

Objectives Define the terms oncogene, proto-oncogenes and growth factors giving examples. Describe the mechanisms of activations of proto- oncogenes and their roles in carcinogenesis. Reference: Textbook of Medical Biochemistry, 7 th edition. Section 7, chapter46 (Biochemistry of cancer). Pages:

Define proto-oncogenes oncogene,and growth factors * A proto-oncogene is a normal gene that can become an oncogene due to mutations or increased expression. The proto-onncogenes converted to ocogenes and develop cancer.expression * A mutant proto-oncogene whose protien product is involved in the transformation of normal cell to cancer cell. * An oncogene can be defined as an altered gene whose product acts in a dominant manner to accelerate cell growth or cell division.

Carcinogenesis Oncogenes and Tumor Suppressor Genes In normal cell, two categories of cell regulatory genes: Proto-oncogenes (cellular oncogene, c-onc) Tumor suppressor gene Proto-oncogenes  oncogenes  increase growth rate  cancer Tumor suppressor genes  inactivated  cancer Proto-oncogenes code for: Growth factors Receptors Signal transduction factors

Differences between oncogenes & Tumor suppressor genes OncogenesTumor suppressor genes Mutation in one of the two alleles is sufficient Both alleles must be affected Gain of function of a protein that signals cell division Loss of function of protein Mutation arises in somatic cells, not inherited Mutation present in germ cell (inherited ) or in somatic cell Some tissue preferenceOften strong tissue preference

NORMAL CELL Growth factor Growth factor receptor Signal transduction Activation of transcription cytoplasm nucleus

Relationship between gene products of proto oncogene Growth factors eg IGF Growth factor receptors Eg erb-2, ret Signal transducing factors Eg cytoplasmic kinases DNA binding proteins concerned with transcription cell cycle proteins eg cyclin D

Tumor suppressor gene (antioncogenes): It is a gene that protects a cell from cancer.genecell – Tumor suppressor genes code for – Tumor suppressor genes code for factors that down- regulate the cell cycle P53 Rb p53: it codes for a regulatory protein that turns off cell division when the cell is stressed or damaged. If mutated, runaway cell division More than half of cancers has a mutated or missing p53 gene

NEOPLASTIC CELLS Increased In growth factor Increased In growth factor receptors Increased in signal transduction Increase in activation of transcription

– Enhancer insertion – Promoter insertion – translocation – gene amplification – point mutation How does proto-oncogenes get activated into oncogenes?

Point mutations, insertions or deletions that give rise to an overactive gene product or lead to an increase in transcription. Gene amplification leading to additional copies of proto-oncogene Chromosomal tranlocation that causes a proto- oncogene to move to a different chromosomal site associated with increased expression or to fuse with another gene to produce a protien that has oncogenic aactivity.

Viral oncogenes RNA Retrovirus: Produces DNA provirus which contain viral oncogene (v- onc) DNA virus: DNA viruses form stable association with host cell genome.

A Reverse transcriptase ( RT) is An enzyme used to generate complementary DNA (c DNA) from an RNA template, a process termed reverse transcription. It is mainly associated with retrovirusses.

Products of viral oncogenes Viral oncogenesProducts erb-BEpidermal growth factor (EGF) rasGTP binding protein mycNuclear protein modify cell growth srcProtein tyrosine kinase sisTruncated platelet derived growth factor (PDGF)

Growth factors Growth factor is a naturally occurring substance capable of stimulating cellular growth and differentiation, it is usually protein in nature. Types of growth factors: Mechanism of action of growth factors: Endocrine, Paracrine and Autocrine. Action of growth factors:

Types of cancer genes Types of proteins Mutated function Normal function Type of gene Enzymes for mismatch or excision repair Fail to repair DNA mutations Repair DNA mutations DNA repair gene mutation Checkpoint molecules Fails to suppress division Suppresses cell division Tumor suppressor gene Growth factorsPromotes division - abnormal time or cell type Promotes divisionOncogene