Biology 457 & 557 -  Week 12

many other nuclear transcription factors that have oncogenic potential

what about other genes or their corresponding proteins which can prevent the effects of

these genes are known as

control abnormal cell growth (dysregulated cell cycle control)

generally, this loss of activity occurs by a somatic mutation and this mutation creates a

            could inherit a mutant allele (predisposition to cancer) and then much later, get another

cell cycle control proteins:

all the processes we have discussed with regards to control of the cell cycle

cyclins, Cdks are checkpoint regulators and get mutation in one of these genes

approximately 12 tumor suppressor genes

they include:

1. pRb (product of the retinoblastoma susceptibility gene) functions as a signal transducer

            in cases of retinoblastoma, a type of heritable cancer where tumors form within the retina

one mutation is inherited (no phenotypic effect) and the other mutation occurs later

pRb inhibits transcription factors that are required for the expression of genes involved in

the first clues as to how it might work came from studies on the interaction of viral proteins with pRb

            it was determined that oncogenic viral proteins bind to, and thereby

additionally, it was determined that pRb function is regulated by

            it is underP in G0/G1, hyperP late in G1 through S and deP as the cell

            leaves mitosis

various cyclin/Cdk molecules phosphorylate pRb at

in its underphosphorylated form, pRb is active and can bind transcription factors

and viral proteins and when fully phosphorylated

pRb does not act directly to control transcription

normally, pRb binds to many cellular proteins but specifically targets the E2F

family of transcription factors

also found that pRb-E2F complexes down-regulate the expression of many

most mutations in pRb result in a truncated unstable protein

thus, phosphorylation or oncoprotein-mediated release of E2F from its

2. p53 is a transcription factor that regulates the normal cell growth cycle by activating

transcription of genes that control

            exerts its function during the

            however, p53 is not necessary for

            but p53 is necessary to

            certain viral oncoproteins also target p53 (like that mentioned for pRb)

            other viral proteins mark it for degradation

            p53 functions as a

            a major role of p53 has been termed “the guardian of the genome” where levels of

            p53 increase in response to

actually, p53 induces transcription of a gene encoding a 21 kd protein that

interacts with and

            specifically, inhibit complexes with Cdk2 & 4, which are kinase

            complexes responsible for

            p53 induces G1 arrest by keeping pRb in its

            p53 can also enhance transcription from the pRb promoter

if repair is not possible, p53 induces programmed cell death or apoptosis

            can have a point mutation, deletion or insertion

            these mutation are

these mutations include missense mutations which cause loss of

thus, if cells deficient in p53 do not arrest in G1 and proceed to replicate damaged

DNA, this will result in an

p53 can also induce apoptosis after cellular exposure to

3. BRCA1 & 2 are large proteins (>200 Kb & >400 Kb respectively) and are thought to be transcription factors

            they both contain a zinc finger region

deletions within exons in these genes drastically decreases embryonic growth and

they may function as

expressed abundantly in testis, thymus and breast and ovary tissues and actually

been found to be

mutations in these genes predispose to breast cancer and inheritance of a BRCA1

mutation carries

usually a frameshift mutation (small deletion/insertion) or production of a stop

codon (makes a functionally inactive protein) and location of the mutation

4. INK4 proteins (inhibitor of Cdk4; 4 genes, A, B, C, D) are cyclin-dependent kinase inhibitors that bind in

            encode proteins p15, 16, 18, 19 that are widely expressed

            of most importance is p16 (also called multiple tumor suppressor 1/MTS1)

            correlation between pRb and p16 expression

            mutations (deletions and nonsense mutations) within the INK4A gene locus occur

in

            just another ex: of how interrelated tumor suppressor genes are to

The Multistep Nature of Cancer

research suggests that to drive a cell through the various stages preceding the production of a tumor in vivo requires

            upwards of

in vitro studies support the notion that cellular transformation is at least a two-step process

            one oncogene is needed for

ex: when rat embryonic fibroblast cells are transfected with a ras oncogene,

            if these same cells are transfected with both ras and myc, the cells are

            same is true if these oncogenes are introduced back into the germ line of the

mouse genome (in vivo)

by itself, myc causes tumors only after 100 days in a few mice

when myc- and ras-expressing transgenic mice are crossed,

            thus it appears that 2 classes of transforming function can be defined:

            because Ras proteins are cytoplasmic and Myc proteins are nuclear,

            however, this distinction can be somewhat clouded because if either oncogene is

            highly over-expressed

            thus high levels of oncoproteins may have different effects from low levels and

            the transformation of a given cell may be affected by

            ex: 3T3 cell line

in humans, the appearance of tumors suggests a similar scenario where many different

events conspire together to cause cancer

            this may explain why most cancer

            such mutations may be either dominantly acting

several combinations of oncogenes and tumor suppressor genes associated with some types of human cancers