Infectious Causes of Cancer Flashcards
1
Q
Carcinogenesis background?
A
- non lethal genetic damage
- regulatory genes
- oncogenes
- tumor suppressor genes - genes regulating cell death (apoptosis)
- DNA repair genes
2
Q
Steps leading to malignant neoplasm? (3)
A
chart
3
Q
Protooncogenes vs oncogenes?
A
- proto- normal
- oncogenes- same gene but abnormal
- 1000s of oncogenes are known
- only need one of two alleles for protooncogenes to become oncogenes
- autosomal dominant expression, mutated allele takes over
4
Q
Actions of oncogenes? (5)
A
pic
5
Q
Growth factors mutations?
A
- mutations in genes encoding growth factors
- growth factor could be involved with turning on cell activity
- increased growth factor production alone is not sufficient for neoplastic transformation
- c sis encodes B chain of PDGF
- astrocytomas and osteosarcomas produce PDGF
- same tumors express receptors for PDGF autocrine stimulation
6
Q
Growth factor receptor mutations?
A
- several are transmembrane proteins
- oncogenic versions
- associated with persistent dimerization and activation without binding to growth factors
- result- constant mitogenic signaling
- higher abundance- amplification of protein, too much
- normal growth factors will bind to all receptors of same cell, leads to over activation
7
Q
Mechanisms of growth factor receptor activation in human tumors?
A
- most common is over expression of receptors
- gene amplification
- 3 members of EGF receptor family commonly involved
8
Q
Normal growth factor vs abnormal, over expression? (9,10)
A
pics
-stimulate angiogenesis
9
Q
Inhibiting drugs of over expression of receptor? (11)
A
-binds receptor to prevent growth factor from binding it
10
Q
Signal transduction proteins mutations? (14)
A
- Ras family of guanine triphosphate (GTP) binding proteins
- 10 to 20% of all humans tumors are mutant Ras
- mutation of Ras gene is the single most common abnormality of dominant oncogenes in human tumors
- in inactive state, Ras binds GDP, upon growth factor stimulation, Ras is activated by exchanging GDP with GTP - activated Ras excites MAP kinase path, binds to Raf1
- excited MAP kinases activate nuclear transcription factors, initiate mitogenic response - GAPs bind Ras, increase GTPase activity of Ras 1000 fold
- mutant Ras- GAPs still bind but no increased GTPase activity - Ras also has some control on level of cyclin dependent kinases to effect cell cycle regulation directly
11
Q
process of Ras stimulation normal? (14)
A
- growth factor activates growth factor receptor to activate signal transduction process
- through bridging protein, inactive Ras protein is stimulated, farnesyl membrane anchors protein to membrane
- has GDP bound - inactive Ras drops its GDP and becomes bound to GTP
- Ras is now active
- binds to Raf1 and GAP proteins to help active Ras become more active
- activity level is 1000 fold more
- needs to cleave GTP, signals to cell to undergo signal transduction to signal other proteins to activate transcription factors in nucleus
12
Q
Process of Ras stimulation abnormal? (14)
A
- active Ras is bound by GTP but stays bound to it
- it stays activated to continue sending signal to cell for transcription in nucleus
- Gap proteins can be abnormal, cannot increase activity of Ras and stays on
- GAP is made by tumor suppressor gene, controls ability of Ras to cleave phosphate group off GTP
- Ras is oncoprotein from oncogene
13
Q
Nuclear transcription proteins?
A
- many oncoprotein have been localized to nucleus (myc, myb, jun, fos)
- myc gene is most commonly involved in human tumors
- normally an early response gene induced when cells are signaled to divide
14
Q
Cyclins and cyclin dependent kinases? (17)
A
- mutations of genes encoding these are found in several human cancers
- cyclin D and CDK4 (CDK6) are over expressed in many cancers, more so than any other cyclins
- cyclins bind with kinases and become phosphorylated
15
Q
CDKs? (18)
A
- phosphorylation event for retinoblastoma protein
- poorly hypophosphorylated, its active, it is bound to other proteins - when phosphorylated it is inactivated
- releases other proteins - activate DNA pol, hydrofolate reductase, other enzymes involved with DNA synthesis
- S phase, G2 phase, mitosis occurs
- genome is now replicated, divided, now new cell is created
- this process is ongoing
- CDKs are growth promoting so they are oncogenes
- retinoblastoma keeps brake on system so it is a tumor suppressor protein
16
Q
Tumor suppressor genes?
A
- brakes to cell proliferation
- 30 tumor suppressor are known
17
Q
Protein products of tumor suppressor genes?
A
- genes encoding components of growth inhibiting paths
- these paths involved cell proteins at the level of nucleus, cytosol, plasma membrane, and cell surface
18
Q
Known tumor suppressor genes? (21)
A
chart
19
Q
tumor suppressor genes involved in nuclear transcription and cell cycle?
A
- Rb gene
- p53 gene
- BRCA-1 and BRCA-2
20
Q
Rb gene?
A
- first tumor suppressor gene discovered
- pRB is a nuclear protein, plays a key role in cell cycle, active state is underphosphorylated
- active state, brake from G1 to S
- phosphorylation inactivates pRb
- S phase will ensue, during M pRb is again dephosphorylated
- in hypophosphorylated form, pRb binds to E2F transcription factor, together bind to DNA to inhibit S phase genes
- upon deletion or mutation, E2F is released, binds to E2F responsive genes, cell cycle is activated
21
Q
Functions of p53?
A
wild type:
- cell differentiation
- cell cycle arrest in G1
- inhibit DNA replication, helicase activity, Rb phosphorylation
- represses transcription of murine double minute (Mdm2 oncogenes)- Mdm2 normally inactivates wild type p53, acts as oncogene
- apoptosis in response to x irradiation and chemotherapy
22
Q
p21 (Waf1/Cip1)?
A
- cyclin dependent kinase inhibitor of G1
- p21 gene induced by p53 in response to DNA damage
23
Q
BRCA 1 and 2?
A
- associated with breast cancer, ovarian, colon, prostate cancers
- inherited germ line mutations increases susceptibility to breast cancer
- with germ line mutation, greater susceptibility also to epithelial ovarian cancer - 5-10% of breast cancer is familial, 80% due to mutations of these two genes
- mutations of these two genes are rarely found in sporadic breast cancer - functions normally for DNA repair, code for proteins that bind RAD51 gene
- RAD51 is DNA repair protein, surrounds abnormal DNA to try to fix it
- if abnormal BRCA, RAD cannot fix problem of DNA
24
Q
Genes that regulate signal transduction?
A
- APC
- NF-1
25
Q
NF-1 tumor suppressor gene?
A
- NF-1 (neurofibromin protein) regulates Ras
- acts as a GTPase activating protein (GAP), facilitates conversion of active Ras to inactive Ras
- loss of NF-1, Ras stays active, continual signal transduction
26
Q
Adenomatous Polyposis Coli (APC) gene?
A
- germ line mutation of APC, associated with benign tumors
- these are precursors of carcinomas that develop later
- individuals with one mutant allele, numerous polyps found in colon in teens and twenties, overgrowth of epithelial cells
- both copies of gene must be mutated to get tumor development, first tumors are adenomas, more mutations are required to get carcinomas
- 70-80% of non familial colorectal carcinomas and sporadic adenomas have homozygous loss of APC - APC gene codes for APC protein which binds beta catenin (factors in cell involved with cadherin proteins stay bound together and cell to cell interaction) mutated APC lets beta catenin get released from cytoplasm into nucleus to turn on cell cycle
27
Q
Cell surface receptors?
A
- TGF beta suppresses MYC gene transcription
- pRb mediates actions of TGF beta, intermediary for MYC transcription
- if pRb is mutated or lost, no TGF beta suppression
33
Q
General considerations of oncogenes and tumor suppressor genes? (38)
A
oncogenes
- activation event
- L/L = leukemia/lymphoma
34
Q
Viruses known to cause cancer? (40)
A
pic
37
Q
Process of virus attaching to cell and causing cancer? (43)
A
pic
42
Q
HPV infection process, p53? (50)
A
pic
43
Q
HPV infection process, pRb? (51)
A
pic
50
Q
Productive and latent infections? (58)
A
-a lot of them are harbored by WBCs
