Tumor Suppressor Genes

pRB

- Nuclear protein with key role in cell cycle - its active state is underphosphoylated during the G0,G1 phase --> binds to E2F transciption factor, which together bind DNA to INHIBIT S phase genes - Phophorylation of pRB inactivates it, usually during S phase

Functions of p53 (wild type)

- cell cycle arrest in G1 - inhibits DNA replication and helicase activity - inhibits the phosphorylation of Rb (thus keeping it active) - in response to DNA damage, it will activate p21 gene - apoptosis in response to X irradiation and chemo

What is the normal activity of NF-1

Acts as a GAP, to facilitate the inactivation of ras. During a loss of NF-1 function, ras is continually on, stimulating transcription and cell cycling.

Mutations associated with APC first develop in to tumors that are ___________, with more mutations followed giving rise to __________.

Adenomas; carcinomas

bcl-2, bcl-xl are apoptotis or anti-apoptotic?

Anti

How many alleles require damage of a tumor suppressor gene in order to lead to neoplasia?

BOTH alleles *Hereditary "hit" + "second hit"

These two genes are asoociated with breast, ovarian, colon, prostate CA. They encode proteins that normally help w/ DNA repair:

BRCA 1 &2

What cancer is loss of APC gene function most associated with?

Colorectal Carcinomas

Xeroderma pigmentosum is a skin cx that is at risk b/c of what error:

DNA repair - defect in nucleotide excision repair

Upon deletion or mutation of Rb, what happens to E2F?

E2F is released and no bound --> binds to E2F responsive genes activating the cell cycle

Tumor Suppressor Genes

Genes which code for proteins that suppress tumor formation by applying brakes on cell proliferation. (mutation that creates a deficiency would contribute to carcinogenesis)

As tumors progress to more advanced stages, they tend to acquire an increasing number of what?

Genetic alterations

Telemere shortening during mitosis reflects what?

Loss of terminal sequences due to incomplete replication of DNA by DNA polyermase.

What oncogene can lead to the inactivation of p53

Mdm-2

Mutations of the both alleles of this gene will lead to benign neurofibromas:

NF-1 *they can later develop into neurosarcomas *children with the disease have an increased risk of AML

Are mutations in the BRCA genes found in sporadic breast cx?

No

APC Gene normal function:

Normally binds to beta-catenin (a transcriptional factor), which prevents its entry into the nucleus and thus inhibits gene transcription.

DNA microsatellite instability

Repetitive nucleotide sequences - usually cytosine adenine. Instability represents shorter or longer repeats than normal that are not repaired, because DNA mismatch repair genes which act as spell checkers are mutated

"haploinsufficiency"

a situation in which the protein produced by a single copy of an otherwise NORMAL gene is not sufficient to assure function. This is a "modification" to the "two hit" hypothesis.

Germline mutations of APC area associated with what?

benign tumors (usually polyps) *BOTH copies of the gene must be mutated to get tumor development.

Telomerase

enzyme that adds TTAGGG nucleotide sequences to the ends of chromosomal DNA to compensate for loses. In normal somatic cells, this is not present, and the cell will usually stop dividing when the telomeric ends are shortened to a critical length. Some cx cells become immortalized b/c they express telomerase activity and proliferate indefinently

miRNA

microRNAs are small single-stranded RNA molecules that can bind to mRNA; they can degrade mRNA or block its translation

What other tumor suppressor gene regulates the activity of TGF-b?

pRB

bax, bad, bid, bcd-xs are apoptotic or anti?

pro-apoptotic

Rb gene, p53 gene, BRCA1/2 are all involved with what type of tumor supression?

regulation of transcription and cell cycle

TGF-beta normal function

to supress transcription of myc.

PTEN gene:

tumor suppresor that is a PI, which can inhibit cellular proliferation, survival and grwoth by inactivating PI 3 Kinase dependent signaling. *Animal studies have shown that loss of just one copy of PTEN gene is enough to begin the process of uncontrolled cell growth

Roughly how many tumor suppressors are there?

~30

What % of breast cx is familial?

~5-10%. Of that, 80% are due to mutations in BRCA genes.