12 Cancer

• 1. tumor suppressors
• 2. proto-oncogenes

• • Suppressors: analogous to the “breaks” of a car in reference to the cell cycle
• • Oncogenes: analogous to a car’s accelerator in terms of the cell cycle

• • encode proteins that help control cell growth & proliferation
• • such proteins generally exert a REPRESSIVE effect on the cell cycle
• • proteins encoded by tumor suppressor genes: p53, pRb, WT1, BRCA1, BRCA2, NF1, APC, PTEN

• • a term that refers to more than 100 forms of disease
• • hallmark of the common cancers: disordered proliferation, growth, & differentiation of cells
• • is a genetic disease - many cancers are caused by mutations; generally happens to people as they age because they’ve accumulated DNA changes
• - mistakes can happen because of replication of because of environmental insults

• rare tumors that arise from neural precursor cells in the immature retina
• • caused by missing Rb gene (tumor suppressor gene found on chromosome 13)
• • individual with a deletion of one RB+ allele is predisposed to develop retinoblastoma; loss of the other RB+ allele in somatic cells induces tumor formation
• • an unusually small number of mutations are required to form retinoblastomas
• • there are 2 forms of the disease, one hereditary, the other not

• • when not phosphorylated, it holds E2F protein in place, preventing movement from G1 → S phase (E2F turns on a bunch of S-phase specific transcription factor genes)
• • when cyclin D or E/Cdk phosphorylates pRB, it becomes INACTIVE & releases E2F (which in turn can now go on to turn on a lot of S phase genes)

True: loss of both alleles is necessary for tumor formation; this is true of most tumor suppressors, with the exception of p53

FALSE: RB is a tumor suppressor gene

• • tumor suppressor that is a substrate for many “stress-related” phosphorylation events
• • phosphorylation is a process that helps to stabilize p53
• • p53 is usually created & degraded very rapidly EXCEPT when there’s stress (eg. DNA damage, oncogene expression) → then it’s phosphorylated & stabilized to respond

• 1. G1/S arrest (via p21 transcription)
• 2. apoptosis
• *clinical correlate: sarcomas, carcinomas

the fact that they don't undergo apoptosis (the decision to kill off a cell is lots of times p53 dependent)

regulatory regions found on genes that can be regulated by p53; also called enhancers

gene turned on by p53 that when transcribed produces a protein that halts cell cycle in G1 by binding to Cyclin/Cdk complexes

• • this allows for DNA repair to take place
• • p21 also binds to PCNA & is able to inhibit progression of replication forks
• • *without p53 no p21 protein is made → cell cycle progresses with damaged DNA*

• RB → Retinoblastoma
• p53 → Sarcomas, Carcinomas
• NF1 → Neuroblastoma
• APC → Colon, Stomach
• BRCA 1 → Breast Cancer

• • altered components of pathways that activate cell division in response to growth factor stimulation
• • mutated copies of proto-oncogenes
• • only 1 of the cell’s 2 gene copies needs to be altered (a dominant effect)

signal transduction: movement of signals from outside the cell to the nucleus

ONLY ONE (dominant)

type of tyrosine kinase receptor involved in signal transduction; has enzymatic activity that can start a signal transduction cascade when it’s phosphorylated

• 1. Excess growth factors
• 2. Defective growth factor receptors
• 3. Defective signaling molecules
• 4. Altered regulation of transcription factors

• the sis oncogene (simian sarcoma)
• • was originally identified in a transforming retrovirus
• • is able to induce signal transduction

a modified form of the EGF receptor that constitutively produces intracellular signals even in the absence of EGF

• • EGF (epidermal growth factor) is a small protein that stimulates cell division
• • ErbB is an oncogene that encodes a modified form of the EGF receptor
• • in these onogene-derived receptors, an intracellular stimulatory signal is produced even in the absence of EGF
• • breast cancer cells often contain mutant ErbB receptors

• • a type of G protein (cytoplasmic signaling molecule)
• • when RAS is bound to GDP it’s in the off state
• • when RAS is bound to GTP it’s active
• • on state is meant to be transient - can convert from on to off simply by hydrolyzing GTP → GDP
• • proteins that do this conversion are GAPs (GTPase activating proteins)
• • mutant forms of RAS are “locked” into the GTP form therefore they’re always on (account for ~25% of cancers)
• - tumors become independent of growth factor signals & there’s excessive signal transduction to the nucleus

ACTIVE!

mutations in the GTPase domain of RAS will reduce the protein's ability to hydrolyze GTP; this results in constitutively active RAS and constituitive protein kinase cascades

• • a protein encoded by the NF1 gene that contains a GAP (GTPase activating protein) domain
• • the disease is associated with defective signal transduction, possibly through RAS
• • Neurofibromatosis is associated with café-au-lait spots & benign neurofibromas (caused by mutated Neurofibromin)

• a tumor suppressor gene
• • it contains a GAP (GTPase activating protein) domain

• • NF1 deletions lead to a loss of the Neurofibromin GAP domain activity
• • this results in neurofibromin not being able to hydrolyze RAS' GTP
• • RAS will be "stuck" in its on position, excessively signaling to the nucleus

• complex composed of transcription factors Fos & Jun
• • they form a heterodimer prior to binding to DNA
• • AP1 binds promoter & enhancer elements & induces growth-dependent genes

• a mutation that will affect the transient nature of Fos & Jun expression may lead to constitutive expression of these proteins
• • as a result, cell growth will be continuous instead of transient

• • encodes a transcription factor that regulates the expression of ~15% of all genes
• • Tx factor protein MYC binds to enhancer sequences (E-boxes) & recruits histone acetyltransferases (HATs - open up chromatin, gene transcription is turned ON)
• • mutated forms of Myc are found in many cancers
• • they cause up-regulation of many genes, some of which are involved in cell proliferation

• • caused by a translocation between chromosome 8 & either chromosomes 2,14 or 22 - these contain genes encoding antibody molecules
• • when translocated, the Myc gene is constitutively expressed
• • *Burkitts is caused by a translocation that up-regulates MYC*

• the mutation is a reciprocal translocation between the c-myc gene & the immunoglobin heavy chain genes (IgH)

• the result is over-expression of Myc and more MYC being made than usual

diverse cancers

• • simian virus 40 (SV40) T-antigen binds the tumor suppressor proteins p53 & pRb
• • this removes the “breaks” & therefore transcription & cell division are more unregulated than they should be
• • cell proliferation is activated by this DNA tumor virus protein

• • this virus does with 2 proteins what SV40 did with 1: it makes 2 proteins, E6 & E7, that bind to tumor suppressor proteins & inactivate them
• • E6 binds to p53 → proteolysis
• • E7 binds to pRB → inactivates pRB (causing E2F to be active)

• • E7 protein binds to pRB to induce the release of the E2F transcription factor
• • this allows E2F to bind promoters & activate the transcription of genes in an unregulated manner

• • viral E6 protein binds to human p53 & induces the proteolysis of p53 via the ubiquitin pathway
• • this allows the cell to both go through the cell cycle without checking for DNA damage & evade apoptosis

E1

E2

• 1. Self sufficiency through growth signals (eg. RAS activation-always bound to GTP)
• 2. Insensitivity to anti-growth signals (eg. loss of pRB, retinoblastoma suppressor)
• 3. Evasion of apoptosis (produce IGF survival factor, or missing/mutated p53)
• 4. Limitless replicative potential (eg. telomerase turned on)
• 5. Sustained angiogenesis (constant blood supply to tumor; VEGF)
• 6. Metastasis and tissue invasion
• • several mutations, over time, can lead to cancer; doesn’t just occur because of one mutation
• • all cancers have same common hallmarks
• • genetic instability can also be associated with cancer

APC → no apoptosis, no cellular breaks, full blast acceleration