Balbeer Singh1248126

SZABIST, Karachi

Oncogenes

Introduction

• Onco means Cancer

• Oncogene is a gene which in certain circumstances can

transform a cell into a tumor cell.

• A Proto-oncogene is a normal gene that can become an

oncogene due to mutations or Increased expression

• The resultant protein encoded by an oncogene is termed

Oncoprotein

Proto-oncogene “Mutation” Oncogene

History

• The term “Oncogene" was coined in 1969 by George Todaro

and Robert Heubner. Of National Cancer Institute.

• The first confirmed Oncogene was discovered in 1970 and

was termed src

• In 1976 Drs. Dominique Stehelin, J. Michael and Harold E.

Varmus of the University of California demonstrated that

oncogenes were activated Proto-Oncogenes, found in many

organisms including humans

Functions of Proto-Oncogene

• Help to regulate Cell growth and differentiation

• Involved in Signal Transduction

• Involved in execution of Mitogenic Signals

Activation

The proto-oncogene can become an oncogene by a relatively small modification of its original function. There are three basic methods of activation:

• A mutation within a proto-oncogene, or within a regulatory region (for example the promoter region), can cause a change in the protein structure.

• An increase in the amount of a certain protein• A chromosomal Translocation(another type of Chromosome

abnormality)

Mechanisms of Oncogene Activation

1. Point Mutation

H-ras [codon 12]

Normal CGC GlyBladder cancer CTC Val

2. Gene Amplification

Double minutes

HSRs

Normal copy Multiple copies

3. Gene Translocation

Ex. Burkitt’s Lymphoma

On chromosome 18, there's an oncogene called BCL2

In people with a certain kind of leukemia, this gene has been moved in its entirety from

chromosome 18 to chromosome 14.

Result of Oncogenes Activation

Overproduction of growth factors

Flooding of the cell with replication signals

Uncontrolled stimulation in the intermediary pathways

Cell growth by elevated levels of transcription factors

Cancer

Classification of Oncogene

Secreted Growth Factors • c-sis, hst

Cell Surface Receptors• erb B, fms, ret, trk, fes, fms

Intracellular Transducers• c-src, c-abl, mst, ras

DNA-binding Nuclear Proteins• myc, jun, fos

Regulators of the Cell Cycle• bcl, bax, bad

Examples of Oncogenes: More Monsters due to Point Mutations

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 carcinomaVal Ala Gln bladder

carcinoma

K-ras Cys Ala Gln lung carcinomaArg Ala Gln lung carcinomaVal Ala Gln colon

carcinoma

N-ras Gly Ala Lys neuroblastomaGly Ala Arg lung carcinoma

Examples of Oncogenes: More Monsters due to Gene Amplification

Oncogene Amplification Source of tumor

c-myc ~20-fold leukemia and lung carcinoma

N-myc 5-1,000-fold neuroblastomaretinoblastoma

L-myc 10-20-fold small-cell lung cancer

c-abl ~5-fold chronic myoloid leukemia

c-myb 5-10-fold acute myeloid leukemiacolon carcinoma

Examples of Oncogenes: More Monsters due to Translocation

Neoplasm Translocation Proto-oncogene

Burkitt lymphoma t(8;14) 80% of cases c-myc1

t(8;22) 15% of cases t(2;8) 5% of cases

Chronic myelogenous t(9;22) 90-95% of cases bcr-abl2

leukemia

Acute lymphocytic t(9;22) 10-15% of cases bcr-abl2

Leukemia

It is easy to kill cancer, but the challenge is keeping the patients

alive at the same time