OncogenesOncogenesDr.CSBR.Prasad, M.D.,

Four classes of normal regulatory genes

• Growth-promoting Proto-oncogenes, • Growth-inhibiting Tumor suppressor genes, • Genes that regulate Apoptosis, and • Genes involved in DNA repair

They are the principal targets of genetic damage

Oncogenes encode proteins that control Cell proliferation,

Apoptosis, Or both

Products of oncogenes

The products of oncogenes can be classified into six broad groups:

1.Growth factors2.Growth factor receptors 3.Transcription factors4.Signal transducers5.Apoptosis regulators and 6.Chromatin remodelers

Activation of oncogenes

They can be activated by structural alterationsresulting from:• Mutation or gene fusion • by Juxtaposition to enhancer elements or • by AmplificationTranslocations and mutations can occur as initiating

events or during tumor progression, whereas amplification usually occurs during progression

Transformation & Progression of cancerTransformation & Progression of cancer

Transformation & Transformation & Progression of Progression of

cancercancer

Two main properties of cancers

They are:• Autonomous &• Eternal

Oncogenes

Genes that promote autonomous cell growth in cancer cells are

called oncogenes

In short, cancer causing genes

Terms

• Proto-oncogenes

• Oncogenes

• Cellular oncogenes

• Oncoproteins

Genes that promote autonomous cell growth in cancer cells are called

oncogenes

Unmutated cellular counterparts of

oncogenes are called proto-oncogenes

Produced by oncogenes, resemble the normal products of proto-oncogenes except that oncoproteins are often

devoid of important internal regulatory elements, and their

production in the transformed cells does not depend on growth factors or

other external signals

The sequential steps that characterize normal cell proliferation

Under physiologic conditions cell proliferation can be readily resolved into the following steps:   

• The binding of a growth factor to its specific receptor   • Transient and limited activation of the growth factor receptor, which, in

turn, activates several signal-transducing proteins on the inner leaflet of the plasma membrane   

• Transmission of the transduced signal across the cytosol to the nucleus via second messengers or by a cascade of signal transduction molecules   

• Induction and activation of nuclear regulatory factors that initiate DNA transcription   

• Entry and progression of the cell into the cell cycle, ultimately resulting in cell division

Proto-oncogenes, Oncogenes, and OncoproteinsProto-oncogenes, Oncogenes, and Oncoproteins

Proteins encoded by proto-oncogenes may function as growth factors or their receptors, signal transducers, transcription factors, or cell cycle components

Oncoproteins encoded by oncogenes generally serve functions similar to their normal counterparts

However, the oncoproteins endow the cell with self-sufficiency in

growth

Growth Factors• Most soluble growth factors are made by one cell

type and act on a neighboring cell to stimulate proliferation - paracrine action

• Cancer cells, however, acquire the ability to synthesize the same growth factors to which they are responsive, generating an autocrine loop

• Note: – In most instances the growth factor gene itself is not altered or

mutated– They are forced to secrete large amounts of growth factor

Growth Factors

Increased growth factor production is not sufficient for neoplastic transformationBut, growth factor driven proliferation may contributes to spontaneous or induced

mutations in the proliferating cell population

Growth Factor Receptors• GF receptors are transmembrane proteins with

an external ligand-binding domain and a cytoplasmic tyrosine kinase domain

• GF binding results in dimerization of and tyrosine phosphorylation of several substances down the signalling cascade

• The oncogenic versions of these receptors are associated with constitutive dimerization and activation without binding to the growth factor

Growth Factor ReceptorsGrowth factor receptors can be constitutively

activated in tumors by multiple different mechanisms:–Mutations–Gene rearrangements–Overexpression

Growth Factor ReceptorsExample: RET oncogeneIn MEN-2A: mutations in the RET extracellular domain

cause constitutive dimerization and activation, leading to medullary thyroid carcinomas and adrenal and parathyroid tumors.

In MEN-2B: mutations in the RET cytoplasmic domain alter the substrate specificity of the tyrosine kinase and lead to thyroid and adrenal tumors without involvement of the parathyroid

Growth Factor Receptors

Example: c-Kit, PDGFR oncogene• Greater than 90% of GIST have a

constitutively activating mutation in the receptor tyrosine kinase c-KIT or PDGFR, which are the receptors for stem cell factor and PDGF, respectively

• Targeted therapy: Imatinib

Signal-Transducing Proteins

• Most such proteins are strategically located on the inner leaflet of the plasma membrane, where they receive signals from outside the cell (e.g., by activation of growth factor receptors) and transmit them to the cell's nucleus

Eg: RAS family of guanine triphosphate (GTP)-binding proteins (G proteins)

Signal-Transducing Proteins - The RAS Oncogene

Alterations in Nonreceptor Tyrosine Kinases

• Non-receptor-associated tyrosine kinases normally function in signal transduction pathways that regulate cell growth

• Mutations take the form of chromosomal translocations or rearrangements that create fusion genes encoding constitutively active tyrosine kinases

Eg: c-ABL tyrosine kinase: BCR-ABL fusion gene - constitutively active, oncogenic BCR-ABL tyrosine kinase - Imatinib

ABL-BCR fusion in CML

Transcription Factors

• A host of oncoproteins, including products of the MYC, MYB, JUN, FOS, and REL oncogenes, are transcription factors that regulate the expression of growth-promoting genes, such as cyclins

• Of these, MYC is most commonly involved in human tumors

Transcription FactorsThe MYC Oncogene (Chr#8)

Range of activities modulated by MYC:

• > cell motility, • > telomerase activity, • histone acetylation, • < cell adhesion,• > protein synthesis, • < proteinase activity,changes that enable a high

rate of cell division

Cyclins and Cyclin-Dependent Kinases

END