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, 7th edition. Section 7, chapter46 (Biochemistry of cancer). Pages:737-744.

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.

* 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 geneProto-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

Oncogenes Tumor 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 preference Often strong tissue preference

NORMAL CELLGrowth factorGrowth factor receptor

Signal transduction

Activation of transcription

cytoplasm

nucleus

Relationship between gene products of proto oncogene

Growth factors eg IGFGrowth factor receptors Eg erb-2, ret

Signal transducing factorsEg 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. – Tumor suppressor genes code for factors that down-

regulate the cell cycle• P53• Rbp53: it codes for a regulatory protein that turns off cell division when the cell is stressed or damaged.If mutated, runaway cell divisionMore than half of cancers has a mutated or missing p53 gene

NEOPLASTIC CELLS

IncreasedIn growth factor

IncreasedIn growth factorreceptors

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 oncogenesRNA 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 oncogenes Products

erb-B Epidermal growth factor (EGF)

ras GTP binding protein

myc Nuclear protein modify cell growth

src Protein tyrosine kinase

sis Truncated 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 proteinsMutated functionNormal functionType 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