rare tumors that arise from neural precursor cells in the immature retina caused by missing Rb gene (chrom 13, tumor suppressor gene); only a small number of mutations are required to form retinoblastomas; disease can either be hereditary or not
tumors produce and secrete:
proteolytic enzymes
Mutations in what two types of genes play major roles in triggering cancer?
1) tumor suppressors
2) proto-oncogenes
What is the difference between carcinomas, sarcomas, leukemias and lymphomas?
Carcinomas arise from epithelial cells
Sarcomas: connective tissues, muscle, cartilage, fat, or bone
Leukemias and lymphomas: blood cells
What are tumor suppressor genes?
genes that encode proteins that help control cell growth and proliferation
such proteins generally exert a REPRESSIVE effect on the cell cycle
What are some examples of proteins encoded by tumor suppressor genes?
p53, pRb, WT1, BRCA1, BRCA2, NF1, APC, PTEN
pRB
phosphoPROTEIN encoded by RB gene located in nucleus that in its UNphosphorylated state blocks progression through the cell cycle
True or False: having one functional allele of Rb is protective against cancer?
True: loss of both alleles is necessary for tumor formation; this is true of most tumor suppressors, with the notable exception of p53
True or False: the retinoblastoma (Rb) gene is a proto-oncogene?
FALSE: RB is a tumor suppressor gene
My Brother Says All Goldman/Sach's Employees Go Deaf
Mitosis/Cyclin B [Cdk 1]
S/Cyclin A [Cdk 2]
G1/S, E [Cdk 2]
G1/Cyclin D [Cdk 4 or 6]
Which cyclins are involved in inactivating pRB?
Cyclins D & E
Which transcription factor is inactive when bound to pRB?
E2F
When pRB is phosphorylated by Cdks, it releases E2F. What is the role of E2F in the nucleus?
It stimulates synthesis of proteins required for the S-phase of the cell cycle (eg. pol-alpha/primase)
p53
a phosphorylated, nuclear protein that has the ability to bind DNA and detects DNA damage; in response it can either cause:
1) G1/S arrest (via p21 transcription)
2) apoptosis
*clinical correlate: sarcomas, carcinomas
response elements (RE)
regulatory regions found on genes that can be regulated by p53; also called enhancers
What is indicative of mutated p53 in cancer cells?
the fact that they don't undergo apoptosis
p21 (or waf1)
gene target by p53 that when transcribed produces a protein that halts cell cycle in G1 phase by binding to Cdk/cyclin complexes
this allows for DNA repair to take place
*without p53 no p21 protein is made --> cell cycle progresses with damaged DNA*
Li-Fraumeni syndrome
a rare inherited cancer condition caused by germline mutations of the p53 gene
Which gene is a target of p53 when it comes to halting the cell cycle?
p21 gene, which codes for a protein that halts the cell cycle in the G1 phase
How does p21 halt the cell cycle in the G1 phase?
It binds to and inhibits the cyclin/Cdk-2 complex, preventing the cell from advancing through the G1/S checkpoint
True or False: the p53 gene is tumor suppressor gene?
True
Match the tumor supressor gene with the type of tumor it suppresses:
RB ---> _____________
p53 ---> ________, _________
NF1 ---> _____________
APC ---> ______, _______
BRCA ---> _____________
Gene Tumor
RB ---> Retinoblastoma
p53 ---> Sarcomas, carcinomas
NF1 ---> Neuroblastoma
APC ---> Colon, stomach
BRCA ---> Breast Cancer
proto-oncogenes
genes that encode growth-promoting proteins (altered components of pathways that activate cell division in response to growth factor stimulation)
What process are many proto-oncogenes involved in?
signal transduction: movement of signals from outside the cell to the nucleus
oncogenes
mutated copies of proto-oncogenes (mutated copies of cellular genes linked with various cancers)
usually DOMINANT
PDGF (platelet- derived growth factor)
type of tyrosine kinase receptor involved in signal transduction; has enzymatic activity
when phosphorylated can start cascade
What are 4 alterations in signal transduction cascades that are linked to cancer?
1) Excess growth factors (eg.
2) Defective growth factor receptors
3) Defective signaling molecules
4) Altered regulation of transcription factors
How many alleles of a proto-oncogene must be mutated before tumor formation can occur?
ONLY ONE
Where are tyrosine kinase receptors located in the cell?
cell membrane (eg. PDGF & insulin receptors)
What oncogene encodes part of the PDGF receptor?
the sis oncogene - originally identified in a transforming retrovirus
Where are steroid receptors located in the cell?
in the cytoplasm or nucleus
upon ligand binding, they migrate to the nucleus where the complex affects gene transcription
What does the erb-B oncogene encode?
It encodes a modified form of the EGF receptor that always produces intracellular signals even in the absence of EGF
Explain the relationship between EGF and erb-B:
EGF (epidermal growth factor) is a small protein that stimulates cell division
erb-B 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 erb-B receptors
RAS protein
when bound to GTP, RAS activates protein kinase cascades
it can normally hydrolyze bound GTP --> switching itself into an inactive GDP-bound form
type of G protein (cytoplasmic signaling molecule)
When bound to GTP, RAS is in its ______ form
ACTIVE!
How does a mutation of the ras gene affect the signaling activity of its protein product, RAS?
mutations in the GTPase domain of RAS will reduce the protein's ability to hydrolyze GTP; this results in constitutively active RAS and constantly occuring protein kinase cascades
What type of gene is the NF1 (neurofibromatosis type 1) gene?
a tumor suppressor gene; it contains a GAP (GTPase activating protein) domain
NF1 gene encodes a protein termed:
Neurofibromin
How does a mutation in the NF1 gene affect the signaling of its protein product, neurofibromin?
NF1 deletion mutations lead to a loss in neurofibromin GAP domain activity
As a result, neurofibromin can't hydrolyze RAS' GTP, meaning RAS will be "stuck" in its on position excessively signaling to the nucleus
AP1
complex composed of transcription factors Fos and Jun; they form a heterodimer prior to binding to DNA
AP1 binds promoter and enhancer elements and induces growth-dependent genes
How does a mutation in the AP1 gene affect cell growth?
a mutation that will affect the transient nature of Fos and Jun expression may lead to constitutive expression of these proteins; as a result, cell growth will be continuous instead of transient
Overexpression of which transcription factor is associated with increased risk of developing Burkitt's lymphoma?
MYC
MYC
a transcription factor that binds to enhancer sequences (e-boxes) & recruits histone acetyltransferases (HATS), regulating the expression of many genes; forces cells through the cell cycle
What is the nature and location of the mutation associated with Burkitt's lymphoma?
The mutation is a reciprocal translocation between the c-myc gene and the immunoglobin heavy chain genes (IgH)
the result is an over-expression of Myc and more MYC being made than usual
Burkitts Lymphoma
caused by a translocation between chromosome 8 and either of 2,14 and 22, chromosomes that contain genes encoding antibody molecules
when translocated, the Myc gene is constitutively expressed
Simian virus 40 (SV40) T-antigen binds which tumor suppressor proteins?
p53 and pRb; removes the breaks and therefore transcription and cell division are more unregulated than they should be
The E6 gene of human papillomaviruses binds to which human tumor suppressor gene product?
p53
The E7 gene of human papillomaviruses binds to which human tumor suppressor gene product?
pRB
How do the viral proteins of human papillomaviruses affect human pRB?
The viral E7 protein binds to pRB to induce the release of the E2F transcription factor, allowing E2F to bind promoters & activate the transcription of genes in an unregulated manner
How do the viral proteins of human papillomaviruses affect human p53?
The viral E6 protein binds to human p53 and induce 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.
Which viral encoded protein in the human papillomaviruses genome is most important for viral genome replication?
E1
Which viral encoded protein in the human papillomaviruses genome is required for viral genome transcription?
E2
What are the six pathologic characteristics of tumor cells?
1. Self sufficiency through growth signals (eg. RAS activation)
2. Insensitivity to anti-growth signals (eg. loss of pRB, retinoblastoma suppressor)
3. Evasion of apoptosis (produce IGF survival factor, or missing or mutated p53)
