chapter 9: molecular biology of cancer Flashcards
when does cancer develop?
- normally, human cells grow and divide to form new cells as the body needs them
- when cells grow old or become damaged, they die and new cells take their place
- cancer develops when a single cell in a tissue undergo transformation, whereby there is mutation in the gene which regulate the cell cycle
- the body’s immune system normally recognises a transformed cell and destroys it
- however if the cell evades destruction by the immune system, it may pass on the mutations to its daughter cells
- old or damaged cells survive when they should die, and new cells form when they are not needed
- these cells can divide uncontrollably via mitosis and may form growths/lumps of tissues called tumours
what are the types of tumours?
- when the tumour is localised in one tissue, it is known as a benign tumour
- however, when these abnormal cells break away from the tumour and are carried in the blood or lymph to other parts of the body,
- secondary malignant tumours are formed
- an individual with malignant tumours is said to have cancer
- the spread of cancerous cells to other parts of the body is known as metastasis
- ## if not treated, the tumour can cause problems by invading normal tissues nearby or by causing pressure on other body structures
how are cancer cells different from normal cells?
cancer cells DO NOT:
- heed the normal signals that regulate the cell cycle
- stop dividing even when growth factors are depleted
- exhibit anchorage dependence (the cancer cells do not need a surface to grow)
- exhibit density-dependent inhibition
( normal cells stop dividing when they come into contact with each other in a crowded environment. cancer cells grow freely over one another and over normal cells)
how does the dysregulation of cell cycle result in cancer?
- in normal tissues, cell growth and division are regulated by checkpoints in the cell cycle
- these regulations involve many regulatory proteins which are encoded by regulatory genes
- proto-oncogenes and tumour-suppressor genes are two groups of genes involved in regulation of the cell cycle
- proto-oncogenes codes for proteins that stimulates cell division
- tumour suppressor genes suppresses the growth of tumour by inhibiting cell division
- when these genes are mutated, dysregulation of the cell cycle occurs, leading to uncontrolled cell division, which results in cancer
what are proto-oncogenes?
- proto-oncogenes encode proteins that stimulate normal cell division
these proteins have essential functions in normal cells, such as:
- growth factors
- growth factor receptors
- transcription factors that promote expression of genes that stimulate cell diviion
- components of signal transduction
-
what happens when the proto-oncogene is converted to a oncogene
if a proto-oncogene undergoes a mutation, such that:
- a hyperactive protein is produced or a degradation resistant protein is produced or
- the normal form of the protein is produced in excessive amounts,
- the mutated proto-oncogene is known as oncogene
- oncogenes result in uncontrolled cell division
- conversion of proto-oncogene to oncogene is a gain-of-function mutation because cell division is stimulated excessively
- a gain-of-function mutation is a dominant mutation
- this is because in a gain-of-function mutation, mutation of only one allele of the proto-oncogene can trigger uncontrolled division
- the one mutated allele will musk the effect of the other normal allele
describe the mechanisms that converts the proto-oncogenes to oncogenes:
genetic change:** translocation of gene from one chromosome to another**
- the proto-oncogene may be moved from its normal locus on one chromosome to another locus on another chromosome
- at the new location, the gene may be under the control of an especially active promotor and other control elements
- this leads to an upregulated gene expression
- the rate of transcription of gene increased (more mRNA), and hence the mRNA is translated more often than normal
- normal protein produced in excessive amounts
describe the mechanisms that converts the proto-oncogenes to oncogenes:
genetic change: gene amplification
- gene amplification processes ( such as unequal crossing-over) may generate multiple copies of the proto-oncogene
- all the copies of the genes are transcribed and translated
- normal protein produced in excessive amounts
describe the mechanisms that converts the proto-oncogenes to oncogenes:
mutation: mutation within a control element
- a mutation can occur in either the promoter or an enhancer that controls the transcription of the proto-oncogene
- the gene is transcribed and translated more often than normal (increased rate of transcription)
- normal protein is produced in excessive amounts
describe the mechanisms that converts the proto-oncogenes to oncogenes:
mutation: within the coding region of proto-oncogene
- a gene mutation in the coding region of the proto-oncogene
there is a change in amino acid sequence of the protein leading to
- amino acids encoded has different R-group properties
- alters R-group interactions
- alters folding of polypeptide chain
- changes tertiary structure of the protein
formation of a hyperactive protein which is
- active all the time and
- resistant to degradation
this hyperactive protein will stimulate cell division even in the absence of stimulatory signals
what is an example of proto-oncogenes?
(not including how it leads to cancer)
- ras gene
- the product of a ras gene is a G protein involved in signal transduction
- it relays a growth signal from a growth factor receptor to a cascade of protein kinases ( phosphorylation cascade)
- and ultimatel results in the sysnthesis of a protein that stimulates the cell cycle
- the nomal ras protein si only activted when a growth factor binds to the growth factor receptor in a signal transduction pathway
how does the ras oncogenes lead to cancer?
**point mutation in the coding sequence of Ras gene
**
- this mutation results in the substitution of an amino acid with a different R-group property
- this would result in a chane in R-group interactions
- which would then change the folding of the polypeptide chain
- this changes the tertiary structure of the ras protein
- this results in a hyperactive form of the protein
- like the ras protein that is always active
- mutant ras protein can trigger the phosphorylation cascade
- resulting in the synthesis of proteins that stimulate the cell cycle
- this leads to excessive cell division even in the absence of growth factor (ligand) binding to the receptor
what is another example of proto-oncogenes?
(case study of Burkitt’s lymphoma)
- the product of the c-myc gene is a specific transcription factor, an activator which binds to enhancer to regulate the transcription of many genes
- including genes coding for proteins involved in normal cell division
- c-myc gene is converted to an oncogene by chromosomal translocation ( a type of chromosomal abberation)
- resulting of a solid tumour of B lymphocytes
- B-lymphocytes are a type of white blood cells that make antibodies
- they are part of the immune system and develop from blood stem cells in bone marrow
how does the c-myc lead to cancer?
- the proto-onconegene, c-myc gene, is moved from its normal locus on chromosome 8 to another locus on chromosome 14
- at the new locus, the c-myc gene is under the control of a very active enhancer
- that normally controls the transcription of highly transcriptional active antibody genes
- the c-myc gene is transcribed and the c-myc mRNA is translated more often than normal
- excessive amounts of c-myc proteins produced
- the overall effect is the uncontrolled cell division of B lymphocytes, forming a tumour
what are tumour suppressor genes? and what happens when they are mutated?
tumour suppressor genes code for proteins that:
- inhibit normal cell division by preventing the stimulating activity of cellular proto-oncogenes or oncogenes
- activate expression of DNA repairing genes to produce DNA repair enzymes
- activate apoptosis (programmed cell death)
- mutation of tumour suppressor gene leads to inactivation of the gene which is a loss-of-function mutation
- because the gene can no longer encode for functional proteins
- inhibiting cell growth and divison is impaired
- loss-of-function mutation is considered as a recessive mutation’this is because both alleles of the tumour suppressor gene need to be mutated/ inactivated to cause the loss of function
- if there is only one mutated allele, the normal allele can still encode sufficient proteins to be effective
- the effect of the mutation is masked by the normal dominant allele
