PROTO-ONCOGENES & ONCOGENES

Proto-oncogenes:-These are the normal cellular genes whose products promote cell proliferation.

                                                                       OR

Proto-oncogenes are genes that normally help cells grow and divide to make new cells, or to help cells stay alive. These are a group of genes that cause normal cells to become cancerous when they are mutated.

• Proto oncogenes have multiple roles but all participate in signalling pathways that drive proliferation.
• These may encode growth factors, growth factor receptors, signal transducers, transcription factors or cell cycle components.
• Proto Oncogenes products regulate the cell growth, division of cells, prevent cell differentiation & regulate apoptosis.

Examples of Proto oncogenes:- Her2gene. This gene codes for a transmembrane tyrosine kinase receptor called Hum – an epidermal growth factor receptor. This protein receptor is involved in the growth repair and division of cell in the breast. Wnt, Myc, Fos/ Jun, RTK, Ras MAP kinase are proto-oncogenes.

Products of proto-oncogenes are essential for cell survival and growth.

Mutations in proto-oncogenes convent proto-oncogenes into constitutively active cellular oncogenes that are involved in tumour development.

Growth Factors:-

• Normal cells require stimulation by growth factors to proliferate.
• Most soluble growth factors → paracine.
• However some cancer cells → autocrine.
• Examples:- Glioblastoma (PDGF and PDGFR).
• Many sarcomas (TGF- && EGFR).
• In tumours in which an autocrine loop is activated, the growth factor gene is usually normal.
• The signals transduced by other oncoproteins cause overexpression and increased secretion of growth factors.
• This causes initiation and amplification of the autocrine loop.

Growth Factor Receptors :-

• A large number of oncogenes encode growth factor receptors of which receptor tyrosine kinase is one of the most important one.
• They are transmembrane proteins with an:-

                     -Extracellular ligand binding domain and

• Receptor tyrosine kinases can be constitutively activated by many mechanisms like

                      -Point mutations.

                      -Gene rearrangements.

                      -Gene amplifications.

ONCOGENESIS:- If a proto-oncogene is abnormally expressed or has undergone a gain-of-function mutation, its protein product will be overly expressed or active. The result is excessive cell division. This mutated form of a proto-oncogene is called an oncogene. The proto – oncogene may be activated as a result of :-

•Point mutations.

• Amplification (increase in proto-oncogene copy number).

•Translocation to a transcriptionally active site (e.g., in Burkitt lymphoma).

•Formation of a chimeric (fusion) gene due to chromosomal rearrangement (e.g., Philadelphia chromosome).

-Protos-oncogenes can encode a very wide variety of proteins with many different functions (cell differentiation genes, signaling molecules, surface receptors, regulatory genes). If, for example, the signaling pathway protein is damaged, the reactivity of the cells to the action of growth factors may change. Significant cell division follows. This can caused by several mechanisms :-

1.) The protein is expressed in cells in which it does not normally appear.

2.) The protein is produced in cells in which normally produce it, but in excessive amounts.

3.) The protein is produced as a form that cannot be regulated by normal mechanisms.

New research has found that the activation of proto-oncogenes to oncogenes can occur via the action of micro RNAs. These are RNA segments of 21-25 nucleotides. They can control the expression of these genes by down-regulating them. Currently, 40 proto-oncogenes are known. of these, 16 of them have been shown to be directly related to tumour growth. These include:-

Proto-oncogene	tissue
Her-2/neu	breast tumours
K-Mas	tumours of the oesophagus, colon and pancreas.
beta-Catenin	tumours of the pancreas and colon
Cyclin E	live tumours.
B-Raf	melanomas

Proto-oncogenes are converted into oncogenes by the following type of mutation Point mutation:- a proto-oncogene is converted into oncogene by insertions or deletions that give rise to overactive

gene product. This mutation also leads to an increase in transcription rate.

The RAS genes, of which there are three in the human genome (HRAS, KRAS, NRAS), were discovered initially in transforming retroviruses. The single most common abnormality of proto- oncogenes in human tumours is Point mutation of RAS family genes.

For example, a change in ‘ras’ oncogene includes (H-ras, K-ras, NRAS). The proto- oncogene code for signal transduction. A GTP-binding protein has GTPase activity that become active to inactive by hydrolysis of GTP to GDP.

→Functions of Proto-Oncogene:-

•Help to regulate cell growth & differentiation.

•Involved in signal transduction.

• Involved in execution of Mitogenic signals

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

-A mutation within a proto-oncogene, or within a regulatory region, can cause a change in the protein structure.

– An increase in the amount of a certain protein.

-A chromosomal translocation.

Mechanism of Oncogene Activation :-

1) Point Mutation

               H-ras          [codon 12]

               Normal      CGC→ Gly

              Bladder cancer CTC →Val

2) Gene Amplification

                Double minutes.

                       HSRs

3) Gene Translocation

 Ex. Burkitt’s Lymphoma.

Result of Oncogenes Activation:-

1.) Overproduction of growth factors.

2.) Flooding of the cell with replication signals.

3.) Uncontrolled stimulation in the intermediary pathways.

4.) Cell growth by elevated levels of transcription factors.

5.) 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.

→Activation mechanisms of proto-oncogenes:-

Oncogenes:- Mutated or over expressed versions of proto-oncogenes that function autonomously having lost dependence on normal growth promoting signals.

Onco-proteins:-A protein encoded by an oncogene that drives increased cell proliferation.

Proto-oncogenes → oncogenes →oncoproteins (constitutively active).

-Oncogenes produce proteins that have the capacity to stimulate growth & 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.

– It was first discovered through the ability of Rous Sarcoma virus (RSV) to cause cancer in chicken.

-All oncogenes have been found in normal cell equivalent genes / proteins & are termed “proto-oncogenes”.

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 PD GF into medium, which causes cells to proliferate in uncontrolled fashion.

→Growth factor receptors:- Oncogenes encoding cell surface receptors that transduce growth promoting signals have bun associated with several types of cancer.

Example, 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 cytoplasmic 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 protein domain on the cell surface exterior & the C-terminal tyrosine protein Kinase is in a permanently turned on state.

Oncogenic retroviruses:-

– Cancer is a genetic disease-oncogenesis consists of processes that result in growth of cells in which mutations have accumulated.

-Viruses are a contributing factor in about  2.0% all human cancers.

-Growth properties & 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 & the need to adhere to a surface.

-They look different, more rounded.

Oncogenic viruses :-

– 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 & division.

– Oncogenic viruses cause cancer by inducing changes that affect cell growth & division.

– Cancer arises from a combination of dominant gain of function mutations in proto- oncogenes & recessive loss of receptors of which receptor tyrosine kinase is one function mutations in tumour suppressor genes.

Oncogenes – Summary

-Oncogenes produce proteins that have the capacity to stimulate growth & proliferation.

-They are dominant or ‘gain of function’ mutations.

– First discovered through the ability of Rous sarcoma virus (RSV) to cause cancer in chickens.

– All oncogenes which have been found in normal cells have equivalent genes / proteins termed as ‘proto-oncogenes’.