Oncogenesis and Tumour Suppressor Genes Flashcards
What are some major functional changes that occur in cancer?
- Increased growth (loss of growth regulation, stimulation of environment promoting growth e.g. angiogenesis)
- Failure to undergo programmed cell death (apoptosis) or senescence
- Loss of differentiation (including alterations in cell migration and adhesion)
- Failure to repair DNA damage (including chromosomal instability)
How do oncogenes and tumour suppressor genes (the two major types of mutated genes) work?
Many oncogenes are normally components of growth factor signalling pathways that when mutated produce products in higher quantities or whose altered products have increased activity and therefore act in a dominant manner.
In cancer, they pick up mutations that mean they are permanently active.
Many tumour suppressor gene products act as a stop signal to uncontrolled growth, may inhibit the cell cycle or trigger apoptosis.
In cancer, pick up mutations that switch the gene off.
Describe viral oncogenesis.
Approximately 15%-20% of all human cancers are caused by oncoviruses.
Viral oncogenes can be transmitted by either DNA or RNA viruses.
DNA viruses can cause lytic infection leading to the death of the cellular host or can replicate their DNA along with that of the host and promote neoplastic transformation.
DNA VIRUSES:
- encode various proteins along with environmental factors can initiate and maintain tumours
RNA VIRUSES:
- integrate DNA copies of their genomes into the genome of the host cell and as these contain transforming oncogenes they induce cancerous transformation of the host.
What are some ways to activate an oncogene?
- mutation
- amplification/ duplication
- translocation
What are the four types of proteins involved in the transduction of growth signals?
Normally:
- growth factors
- growth factor receptors
- intracellular signal transducers
- nuclear transcription factors
How does transduction of growth signals relate to cancer?
The majority of oncogene proteins function as elements of the signalling pathways that regulate cell proliferation and survival in response to growth factor stimulation.
Oncogene proteins act as growth factors (e.g.EGF), growth factor receptors (e.g. ErbB) and intracellular signalling molecules (Ras and Raf).
Ras and Raf activate the ERK MAP kinase pathway, leading to the induction of additional genes (e.g. fos) that encode potentially oncogenic transcriptional regulatory proteins.
Describe the RAS oncogene family.
RAS genes were identified from studies of two cancer-causing viruses: the Harvey sarcoma virus and Kirsten sarcoma virus. These viruses were discovered originally in rats, hence the name Rat sarcoma.
RAS proteins are small GTPases that are normally bound to GDP in a neutral state.
Oncogenic activation of RAS is seen in about 30% of human cancer.
It is the most commonly mutated oncogene.
It involved point mutations in codons 12, 13 and 61.
The consequence of each of these mutations is a loss of GTPase activity of the RAS protein normally required to return active RAS to the inactive RAS GDP.
It converts:
- glycine to valine: bladder carcinoma
- glycine to cysteine: lung cancer
Describe the normal mechanism of the RAS oncogene.
- Binding of extracellular growth factor signal.
- Promotes recruitment of RAS proteins to the receptor complex.
- Recruitment promotes RAS to exchange GDP (inactive RAS) with GTP (active RAS).
- Activated RAS then initiates the remainder of the signalling cascade (mitogen activated protein kinases).
- These kinases ultimately phosphorylate targets, such as transcription factor to promote expression of genes important for growth and survival.
RAS hydrolyses GTP to GDP fairly quickly, turning itself “off”.
Describe the MYC oncogene family.
The MYC oncogene family consists of 3 members: C-MYC, MYCN, and MYCL, which encode c-Myc, N-Myc, and L-Myc, respectively.
They were originally identified in the avian myelocytomatosis virus (AMV).
The MYC oncoproteins belong to a family of transcription factors that regulate the transcription of at least 15% of the entire genome.
Major downstream effectors of MYC include those involved in ribosome biogenesis, protein translation, cell-cycle progression and metabolism, orchestrating a broad range of biological functions, such as cell proliferation, differentiation, survival, and immune surveillance.
Describe the MYC oncogene family (specifically it’s mutated role in cancer).
The MYC oncogene is overexpressed in the majority of human cancers and contributes to the cause of at least 40% of tumours.
It encodes a helix-loop-helix leucine zipper transcription factor that dimerizes with its partner protein, Max, to transactivate gene expression.
Generally, MYC is activated when it comes under the control of foreign transcriptional promoters. This leads to a deregulation of the oncogene that drives relentless proliferation.
Such activation is a result of chromosomal translocation.
Describe another case where chromosomal translocation is responsible for the activation of an oncogene.
Chronic myelogenous leukaemia (CML) accounts for 15-20% of all leukaemias.
95% of CML patients carry the Philadelphia chromosome; that is the product of the chromosomal translocation t(9;22)(q34;q11) generating the BCR-ABL fusion protein.
As a result of this translocation, the tyrosine kinase activity of the oncogene ABL is constitutive leading to abnormal proliferation.
Therapeutic strategies for CML include Imatinib (Gleevac) a tyrosine kinase inhibitor-96% remission in early-stage patients.
Describe retinoblastomas.
Retinoblastoma is a rare childhood cancer (1 in 20,000) that develops when
immature retinoblasts continue to grow very fast and do not turn into
mature retinal cells.
An eye that contains a tumour will reflect light back in a white colour.
This is often called a “cat’s eye appearance”, the technical term for this is leukocoria.
There are two forms of the disease, familial (40%) and sporadic (60%).
The hereditary mutation is on chromosome 13 (13q14), the retinoblastoma 1 (Rb1) gene.
What are loss-of-function mutations?
Mutations that inactivate tumour suppressor genes, called loss-of-function mutations, are often point mutations or small deletions that disrupt the function of the protein that is encoded by the gene.
Describe the retinoblastoma protein RB structure.
The Rb gene family includes three members: Rb/(p105/110), p107 and Rb2/p130
- collectively they’re known as pocket proteins.
pRb is a multi functional protein (110kDa) with over 100 binding partners.
A transcriptional co-factor can bind to transcription factors.
RB functions in diverse cellular pathways, such as apoptosis and the cell cycle; it has also become clear that RB regulates these pathways through the stimulation or inhibition of the activity of interacting proteins.
Therefore, an important starting point for understanding RB function is its structure, which acts as a scaffold for these multiple protein interactions.
Its main binding partner is the E2F transcription factor, interacting with the large pocket.
Other viral oncoproteins can bind to Rb.
What is the role of the retinoblastoma protein RB in the cell cycle?
The main function of Rb is to regulate the cell cycle by inhibiting the G1 to S phase transition.
2 important proteins involved in the cell cyle are:
cyclins and their associated cyclin dependent kinases (cdks).
Passage of a cell through the cell cycle is regulated
cyclins and cyclin dependent kinases (cdks).
Cyclin D is the first cyclin to be synthesized and drive progression through G1 together with cdks4/6.
The G1 checkpoint leads to the arrest of the cell cycle in response to DNA damage.
A key substrate for cyclin D is RB protein.
Cyclin D and E families and their cdks phosphorylate RB.
