Biochemistry of Cancer Flashcards
hallmark of common cancers
- disordered proliferation, growth, and differentiation
- is a genetic disease
heredity of Rb
- having one mutated copy puts you at an increased risk for developing retinoblastoma
- loss of the other copy of the gene causes tumor formation
description of retinoblastoma
- cell type and location
- mutations
- forms
- other types of cancer
- arise from neural precursors in the immature retina
- an unusually small number of mutations are necessary to develop the cancer
- two forms, one hereditary and the other not
- Rb is frequently missing in many types of cancer
E2F
- a TF typically bound by the active form of Rb
- this TF is responsible for sending the cell into a proliferative state
- specifically sending the cell into S phase
mechanism of pRb
- in a nondividing cell, pRB is bound to E2F in the nucleus, inhibiting it from initiating transcription of proteins that will send the cell into s phase
- in a dividing cell, Cyclin D and E and their designated CDK’s will Phosphorylate pRb, causing it to release E2F
- E2F then goes on to initiate transcription of pro-mitotic genes
- most antiproliferative signals are funneled through Rb
p53 is stabilized and increased…
during times of stress
-this is done by phosphorylation of p53
Response elements or enhancer elements
-genes regulated by p53 have these regions and respond to p53
Role of p53 in halting the cell cycle and apoptosis
- DNA damage: p53 then activates p21 which then inhibits Cyclin/CDK complexes, halting mitosis
- Ocogene expression: p53 is activated and tells the cell to begin apoptosis via induction of genes which produce reactive oxygen species (ROS)
p21
- is activated by p53 when it senses damaged DNA
- p21 binds cyclin/CDK complexes which halts the cell cycle
- also is able to bind PCNA to inhibit progression of the replication fork
RB tumor
retinoblastoma
p53 tumor
sarcomas, carcinoma, and more
NF1 tumor
neuroblastoma
APC tumor
colon, stomach
BRAC1 tumor
breast cancer
oncogenes
- due to altered components of pathways that activate cell division in response to growth factor stimulation
- this is typically a dominant effect (only one mutated copy needed)
proto-oncogenes
-typically involved in signal transduction in some way
tumor cells generate many of their own…
growth factors
signal transduction
-tyrosine kinase
- certain receptors penetrate the plasma membrane (ie PDGF receptors = tyrosine kinase)
- phosphorylation of tyr residues allow interaction with other members of the cascade
- signals are meant to be transient
alterations in signal transduction cascades associated with cancer
- excess growth factor
- defective growth factor
- defective signaling molecules
- altered regulation of transcription factors
altered growth factors
-simian sarcoma virus
- the simian sarcoma oncogene was originally identified in a transformaing retrovirus
- the gene encodes part of the PDGF molecule and is able to induce signal transduction
Altered growth factor receptors
-EGF
- mutant forms of the epidermal growth factor receptor are known that constantly stimulate growth even in the absence of EGF
- family members include ErbB/HER2
activation of RAS signalling
- this is a very important signaling molecule
- when bound to GTP, it is active
- When bound to GDP, it is inactive
- GAPs (GTPase activity protein) help regulate its activity
- mutations in RAS reduce GTPase activity, leaving it consitutively on
NF1 gene and neurofibromin
- NFI encoded neurofibromin
- neurofibromin contains a GAP domain
- neurofibromatosis is associated with cafe-au-lait spots and benign neurofibromas
- the disease is associated with defective transduction, possibly through RAS
expression of c-fos and c-jun
- in normal cells there is typically just one copy of each of these TF’s and therefore you get transient growth
- in cancerous cells, there are many copies of both which leads to continuous growth
- these TF’s bind to the AP1 site
Myc
- E boxes
- HATs
- myc encodes a transcription factor that regulates the expression of about 15% of all genes
- it binds to enhancer sequences (E boxes) and recruits histone acetyltransferses (HATs)
- mutated forms of myc are found in cancer cells, this leads to the up-reg of many genes, some of which are involved in prolif
burkitt’s lymphoma translocation
- between 8 and 14
- puts a much stronger promoter associated with myc
- myc is now associated with a IgH promoter
burkitts lymphoma
- chromosomal translocations are associated with leukemia and lymphoma
- in this translocation, myc is placed with IgH and myc is then constitutively expressed
cyclin dysregulation
-excessive or innapropriate expression of cyclins is associated with some malignancies
role of SV40 T-antigen in tumor formation
- viral protein binds both pRb and p53 causing the cell to have no control over the entry into S phase
- Rb is not permitted to bind up E2F and p53 can not act as a safety brake
HPV in forming tumors
- has two proteins involved, E6 and E7
- E6: protein product capable of binding p53 and inducing its proteolysis
- E7: protein product capable of binding pRb and preventing it from interacting with E2F
acquired capabilities of cancers and the examples of genes involved
- self sufficiency in growth signals: RAS
- insensitivity to anti-growth signals: pRb
- tissue invasion and metastasis: inactivated E-Cadherins
- limitless replication potential: overly active telomerase
- sustained angiogenesis
- evading apoptosis: p53
chromosome chaos and cancer
-rearrangement and changes in chromosomes as a whole is thought to play a key role in the development of cancer
