T2 - Neoplasia 3 - Morris (Molecular Basis I)

Front 1

tell between primary cells, immortal cells, transformed cells (objective)

Back 1

These are about cells in culture, but are applicable in vivo. Generally, primary cells die off, immortal cells don't, and transformed cells are cancerous and will cause tumors when injected in mice.

Primary cells are the normal cells in culture. They divide 20-50 times before dying/sensencence, require anchorage, require serum, contact inhibited, flattened morphology, don't make tumors when injected in mice, and have organized cytoskeletons.

Immortal cells are IDENTICAL, except they're IMMORTAL.

Transformed are all OPPOSITE of immortal cells, 'cept they're both immortal (contact independent, litttle serum, rounded, disorganized cytoskeletons, anchorage independent, etc).

Front 2

How do you activate them? Examples? What are the major proto oncogenes? (objective) How

Back 2

You can activate a proto-oncogene by Point mutations - think RAS (kill the intrinsic GTP-ase activity, so always have RAS on (=gas=accelerator).

You can translocate - 9:22 = CML (bcr-able). or 8:14 (burkitt's = Ig + cMYC).

you can amplify - increase number of genes. Up N-myc = more neuroblastoma. up c-erb = more breast cancers.

Insertion - retroviruses, insert promoter in front of oncogene.

Front 3

What are Sis and TGF-a?

Back 3

Sis makes PDGF (platelet derived growth factor), and TGF = transforming factor alpha. So both of these are growth factors.

these are protooncogenes that are overexpressed in lung cancers.

Front 4

we talked about increased growth factor - what genes might result in weird growth factor receptors?

Back 4

ERB - this is the receptor for EGF. Over expression if leads to lung cancers. So this is a proto-oncogene too.

Front 5

so oncogenes can be growth factors, and receptors - what's the next potential oncogene type and what are examples?

Back 5

signal transducers - immediately think about RAS (gas). Inner leaflet G protein - MOST COMMONLY MUTATED ONCOGENE. has active (GTP) and inactive (GDP) forms - remember that point mutations can make it permanently GTP Bound and active.

Front 6

so we have growth factors (sis), their receptors(erb), the signal transducers (ras)...what's next?

while we're at it, talk about anti-apoptosis:

last, cell cycle regulatory proteins:

Back 6

transcription factors! think MYC. these are the guys that force the cell to complete the cell cycle.

remember with myc that we can be talking about BURKITT's lymphoma, which is an 8:14 translocation that puts an Ig promoter in front of the myc gene.

anti-apoptosis, IMMEDIATELY THINK BCL-2 (edit - this is mutated in Follicular lymphoma with the 14:18 T)
BCL-2 binds up and stops BAX/BAX dimer from releasing caspase 9 from the mitochondria and inducing apoptosis. Don't get confused with BCR/ABL in CML.

think cyclin D if you're thinking cell-cycle regulation. overexpression = cancer.

Front 7

if culturing cells, what's a typical sequence to cancer?

Back 7

primary cells have a CRISIS, most die out and a few survive - these are immortal.

eventually some immortal cells get transformed, become cancer causing.

Front 8

compare the basic characteristics of oncogenes and tumor suppressors - talk about inheritance pattern, number mutated, function of the mutant allele...?

Back 8

tumor suppressors: need 2 mutations, so "recessive," OFTEN inherited, are LOSS of function, and tends to "prefer" a tissue.

oncogenes - need 1 mutation, NOT usually inherited, doesn't generally prefer a tissue, and represents a GAIN of function.

Front 9

Where does CML come from? What about Burkitt's Lymphoma?

Back 9

CML = translocation of 9:22, with the BCR/ABL fusion protein (tyrosine kinease that goes to nucleus, ups a lot of genes).

Burkitt's: 8:14 translocation that puts an Ig promoter in front of c-Myc, = cancer.

Front 10

what are the ways that oncogenes can transform cells?

Back 10

generally, you can mess with growth factors themselves, their receptors, the transducers of those growth signals, transcription factors, apoptosis inhibitors, cell cycle regulators.

Front 11

what does promoter methylation have to do with anything?

Back 11

this is about tumor suppressors! it's a way that tumor suppressors can become cancer causing.

perhaps this is what is meant by "epigenetic" changes?

Front 12

What does DCC do?

What does NF-1 Do?

Back 12

deleted in colon carcinoma - this is an adherin-style gene (e-cadherin) that mediates intracellular connections. loss of this allows cells to break off and invade - so it's a TUMOR SUPPRESSOR.

NF1 - this binds to and turns RAS from its GTP bound state to a GDP bound state (turning off the oncogene).

that makes NF-1 a TUMOR SUPPRESSOR - if it's mutated, likely to have permament RAS activation (something also achieved with point mutations to RAS).

Front 13

what does RB do? What virus targets this?

Back 13

RB is a tumor suppressor - it binds up transcription factor EF-2 (and myc), which is needed to encourage the cell to go through the CDK-4/cyclin D stage of the cell cycle. If no RB, lots of EF-2, so the cells can replicate.

when your hear RB, think about HPV's protein E7, which screws up RB, so more Ef-2, so more cell proliferation and cancer.

Front 14

what does P53 do?

Back 14

Couple of big things.
1. It stops cell division after DNA damage happens. So it's a tumor suppressor.

2. In high doses (lots of DNA damage), it induces BAX to kill the cell (another tumor suppressor action).

NOte that Mdm-2 can bind up and kill p53.

Also, HPV factor E6 binds up p53, another way that cancer can be caused.

ALSO - can have DOMINANT NEGATIVE mutations - this means that only it's possible for ONE mutation to be required for p53 dysfunction and tumor formation (weird for tumor suppressor, which usually requires 2 mutations)

Front 15

what proteins/diseases are associated with mutated repair mechanisms?

Back 15

HNPCC (heredetary non-polyposis colon cancer) has mutated hMLH1/2 repair mechanisms. Also, BRCA1 and BRCA2 are involved in the signals involved in DNA repair.

ATM too.

Front 16

what are fanconi's anemia, ataxia-telegenctasia, bloom's syndrome, xenoderma pigmentosum, and HNPCC?

Back 16

fanconi's anemia: problems with DNA repair and anemia? complicated.

bloom's syndrome = lots of random translocations happen all the time.

ataxia-telegenctsia = ATM gene = big time repairer of DNA damage. Also controls the cell cycle. kids have problems with ataxia and small blood vessels in the brain/eye

xenoderma pigmentosum is a problem with NER (nucleotide excision repair) = can't fix thymine dimers from UV radiation. kids are likely to get other mutations, like in p53, and get big bad tumors.

HNPCC - problems with DNA mismatch repair, genes MSH2/MLH1.