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Cancer cells


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what are the characteristics of a cancer cell?
-cancer cells do not respond to normal proliferation controls

-they may invade other tissues

-may relocte to new sites

-fail to self-destruct when abnormal

-may promote blood vessel formation (angiogenesis)
How do cancer cells differ from normal cells ?
-variation in cell size and shape

-enlarged nuclei

-chromosomes look differentt

-lots of nuclei

-atypical mitosis
what are the most common cancers?
-prostate cancer
-breast cancer
-lung cancer
-colon cancer
How are malignant and benign cancers distinguished?
Benign: do not invade other tissue borders-> grow and expand but do not infiltrate

-do not metastisize

-differentiated (resemble tissue of origin

Malignant:metastasis to distant site, invades other tissues
What kinds of molecular defects cause cancer? (2)
-mutations that activate oncogenes which stimulate cell growth

-mutations in tumor supressers that become inactivated which normally regulate cell growth
What are the most important components of cancer-related signal transduction pathways
1)growth factor binds to receptor

2)receptors relay signal to cytoplasmic proteins by phosphorylation

3)cytoplasmic proteins: Ras is activated by receptor tyrosine kinases when it binds GTP

4)Ras transmits the signal to MAP which carries signal from cytoplasm to nucleus

5)MAP phosphorylates transc. factorps that activate transcription of target genes whose gene products promote cell cycle progretion
how does Ras get activated/ deactivated?
-Ras is activated by GNRPs which stimulate release of GDP and bind GTP

-deactivated by GAPs which stimulate hydrolysis of GTP bound
what are the most important components of cancer-related cell cycle regulation?
-CDKs which phosphorylate cyclins

-cyclins degrade in each division cycle in response to signal transduction

-mitotic cyclins bind Cdk during G2(required for mitosis)

-G1 cyclins bind Cdk during G1 (required for s phase)
How are these genes altered in cancer cells? (3)
-w/ cancer there can be an overproduction of cyclin

-tumor suppressor genes are inactivated by a recessive mutation in 1 allele and the loss of the remaining wild type allele->loss of heterozygosity

-P53 can be altered so that it cannot bind to the promoter-changes binding site and prevents the damage response and allowing cell proliferation
What are oncogenes and tumor suppressors and how are they relevant to cancer?
oncogenes:activator and controller of cell growth, ex. Ras

tumor supressor: deactivated in cancer cell, normally stop growth

ex. P53: checkpoint transc. factor, turns on genes involved in apoptosis, an inhibitor of cell cycle progression by inducing p21 which inactivates cdk required for DNA synth.

Rb: controls transc. of genes needed for cell cycle by stopping transc. factors by binding to E2F transc. factor

-CDK can phosph. Rb (inactivating it)which allows the transc. factors to have access to binding sites
What is the mutagenesis model for cancer production
-initial mutation cretes a mutator precuror cell which then produces muatations at high levels

mutator cells have defects in:
cell cycle regulation
dna replication fidelity
dna repair
p53 is activated when?

what does it bind to?

what is its funtion?
activated following DNA damage

binds to promoter

funcions to promote transc. of genes involved in the damage response ex. inhibits g1/ s transition by induces p21 (reduces cdk required
for dna synth)

-also inhibits g2/m transition by lowering intracell conc. of cyclin required for mitosis

How does Rb dissasoc. from E2f which is bound to promoter?
it gets phosphorylated by cyclin/cdk complex which allows E2F to activate transc. which promotes progress to s phase
how does p21 relate to Rb ?
p21 is up-regulated by damage and p53 activation

-it inhibits cdks so Rb remains in active (non phosphorylated form)-growth inhib. state
What celluar systems are defective in early stages of cancer?
coding and regulatory regions of the genes-> mutations lead to alternate proteins or abnormal expression
what types of mutations cause cancer?
-sing base change (point mutation)--may change indiv. aa's or prematurely truncate encoded protein

-insertions/deletions: change reading frame leading to altered protein seq. or truncation

-Genome rearrangements: (translocations) especially in leukemias
-may cause gene activation:
gene is moves to new location where its expression is altered by near-by regulatory sequences

or may cause gene fusion:
piece of gene inserted in another gene sequence so coding seq. is on same reading frame for both genes. Hybrid gene is formed and may be expressed at altered levelsor translation product may have unusual functional properties

-more gene fusion:usually in blood diseases, transcription factor is usually involved causing inapprop. gene expression
How do these mutations affect oncogens and tumor suppressors differently?
oncogenes:in tumors they are activated by mutations which either overproduce protein or allow expression under inaprop. conditions--result in gain of function

tumor suppressors:become inactivated and fail to suppress growth
What steps during DNA replication prevent cancer/
Replicaton errors are from failure of DNA pol to incorp. correct nucleotides

minimize mutations by:

-correct insertion of nucleotides by dna pol

-proofreading by exonuclease

-use of specialized polymerases to replicate past DNA damage (by-pass polymerases)

-post-replication repair process (mismatch repair)
what disease has abnormal by-pass polymerase? and what is the polymerase it's supposed to have ?
XPV: defects in DNA pol n

-prevents accurate by-pass of uv damage and lets a less acc. polym form the bypass resulting in excess mutation
What is mismatch repair and how is it related to cancer?
mismatches are recognized by MutS.

-MutS makes a complex with MutL and Mut H allowing Mut H to nick the DNA

-nucleases remove a strech of DNA including mismatch

-resulting gap is filled by dna pol and sealed by ligase
how does the mismatch system know wich strand to repair?
MutH identifies the unmethylated A and cuts it out
why do we have mismatch repair in colon cancer?
colon tissues are rapidly growing and replicating

-blood cancer also shows mismatch
Colorectal cancer has mutations where?
mismatch repair defects in MutS o MutL
What is nucleotide excision repair and how is it related to cancer?
1)damage recognition by XPA and XPC
3)damage removal
4)gap filling DNA synthesis
what diseases are caused by defects i n this mechanism?
XP:exhibit defects in recognition or incision steps not dna pol or ligase

-TTD and Cockayne syndrom
mutations are found in CSA and CSB
when is XPC needed?
when you don't have transcription, so in general repair and recognition--so mutation is in XP not CS
what are XPD and XPB
they are inside TFIIH and act to target nucletotide excision repair and are needed for promoter recognition by RNA Pol
What is homologous recombination and how is it related to cancer?
homologous recombination repairs breaks in dna

1)dna ends in a break and transformed to ssDNA
2)RAD51 protein is targeted to ssDNA and promotes pairing to homologous duplex

-repairs double strand breaks
How is homologous recomb related to cancer?
Indiv. with muations in BRCA1 and BRCA 2 develope breast cancer

-normal BRCA allele is lost so tumor is homozygous
what happens in absence of BRCA2?
RAD51 promoted homologous recomb is impaird

-in BRCA2 breast cancer cells complex formation between RAD51 and BRCA2 is disrupted and RAD51 remains in cytoplasm
what sorts of genetic diseases make us cancer prone?
XPV-missing bypass polymerase

XP-missing nucleotide excision repair

breast cancer-missing BRCA2 and Rad51 can't function

colorectal cancer-mismatch repair deffects in MutS or MutL

Li-Raumeni syndrome -p53
what is UVB?
sunburn, results in damage to epidermal cells
penetrated deeper than UVB

phot-aging rather than sunburn

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