Chapter 7 - TUmor Suppressor Genes

tumor suppressor genes

Section 7.1 - Cell fusion experiments indicate that the cancer phenotype is recessive

Figure 7.1 - Cell fusion is a technique which causes to cells and their nuclei to merge together
Figure 7.2 - Cell fusion can result in cells with multiple nuclei
Figure 7.3 - Cell fusion can be used as a test for an allele's recessiveness or dominance, in the case of cancers, non-tumor virus cancers are recessive and tumor virus cancers are dominant

Synctium
Polykaryon
Heterokaryon

Section 7.2 - The recessive nature of the cancer cell phenotype requires a genetic explanation

Section 7.3 - The retinoblastoma tumor provides a solution t the genetic puzzle of tumor suppressor genes

Figure 7.4 - A retinoblastoma is the result of a defect in the Rb gene which controls growth in most cell types but leads preferentially to retinoblastomas
Figure 7.5 - Retinoblastomas can occur unilaterally, termed sporadic, or bilaterally, familial.  The familial form of retinoblastoma has a 1/2 chance of being passed on to an offspring and leads to a higher incidence cancers
Figure 7.6 - Alfred Knudson Jr.'s kinetics studies on retinoblastomas revealed that unilateral retinoblastomas are the result of two random events (mutations) while bilateral retinoblastomas are the result of one random event
Figure 7.7 - Children who suffer from familial retinoblastomas do so because one copy of the Rb gene is non-functional, requiring that only the other copy be knocked out.  Those who suffer from sproadic retinoblastomas are born wild-type but suffer from two mutations, one in each copy of the Rb gene.

retinoblastoma
syndrome
sporadic
familial

Section 7.4 - Incipient cancer cells invent ways to eliminate wild-type copies of tumor suppressor genes

Figure 7.8 - A heterozygous somatic cell can leave behind homozygous daughter cells through the act of mitotic recombination.  This explains the occurence of retinoblastomas in heterozygous children
Sidebar 7.2 - It has been found that mitotic recombination and loss of heterozygosity occurs more frequently when two chromosomes are very similar to one another than when they are more different.  This could have implications for cultures that are known for marrying within the same culture.
Figure 7.9 - Gene conversion can occur when DNA polymerase switches template strands when replicating the genome.  This occurs more frequently than does mitotic recombination

Section 7.5 - The Rb gene often undergoes loss of heterozygosity in tumors

Figure 7.10 - a deletion starting at 13q13 and containing parts of 13q14 revealed the location of the Rb gene
Figure 7.11 - Esterase D, an enzyme whose gene is found in the same region as the Rb gene, has two different isoforms corresponding to the allele present.  Gels stained for this enzyme and run using normal tissue and tumor tissue revealed the occurence of loss of heterozygosity
Sidebar 7.3 - Loss of heterozygosity can also occur via nondisjunction and nonhomologous recombination
Figure 7.12 - A Southern Blot of the later cloned Rb gene further proved that loss of this gene was linked to cancer
Why not affect more tissues -> Chapter 8

submicroscopic
hemizygosity
mitotic recombination
null

Section 7.6 - Loss-of-heterozygosity events can be used to find tumor suppressor genes

Figure 7.13 - RFLPs are sites where cleavage by a restriction enzyme can occur in one allele and not the other.  They can be used to detect LOH
Figure 7.14 - Measurements of the rate of occurence of LOH through RFLP indentification can be used to find which chromosomes likely carry tumor suprressor genes
Sidebar 7.4 - PCR can also be used to detect nucleotide polymorphisms through the presence or lack of a PCR product
Table 7.1 - There are a number of tumor suppressor genes that have been successfully cloned

Restrction fragment length polymorphism
Colorectal tumors

Section 7.7 - Many familial cancers can be explained by inheritance of mutant tumor suppressor genes

Cancer predisposition --> Chapter 12
Sidebar 7.5 - Oncogenes are likely not inherited because they are dominant at the cellular level.  Conversely, mutated tumor-suppressor genes can be inherited because they are recessive at the cellular level

gatekeepers
caretakers

Section 7.8 - Promoter methylation represents an important mechanism for inactivating tumor suppressor genes

Figure 7.16 - Maintenance methylases detect methylation on the parent strand of the chromosome and reproduce the methylation pattern on the daughter strand
Figure 7.17 - Methylation of certain areas of the genome can interfere with producion of certain proteins and thus cause cancer
Table 7.2 - Hypermethylation can lead to various cancers
p16^INK4A --> Section 8.4
Figure 7.18 - Hypermethylation is only on step along the road to pthoogenicity, though a major one
BRCA1 --> Section 12.10
Figure 7.19 - different tumor varieties are more likely to methylate different promoter sequences

maintenance methylases
epigenetic
de novo methylases

Section 7.9 - Tumor suppressor genes and proteins function in diverse ways

Rb --> Chapter 8
p53 --> Chapter 9

Section 7.10 - The NF1 protein acts as a negative regulator of ras signaling

Figure 7.20 - Neurofibromatosis is classified as a syndrome because it leads to a number of distinct conditions depending on the patient's genetic background
Figure 7.21 - NF1 serves to stimulate the GTPase activity of Ras
Sidebar 7.6 - It is not always necessary that a cell be homozygous for a cancer gene for tumors to develop

neruofibromas
neurofibrosarcomas
pheochromocytomas
cafe au lait spots
genetic background
haploinsufficiency

section 7.11 - Apc facilitats egress of cells from colonic crypts

Figure 7.22 - Those suffering from familial adenomatous polyposis (FAP) are highly prone to polyp formation
Sidebar 7.7 - 
Figure 7.24 - stem cells at the bottom of crypts in the intestines are slowly pushed outward by nearby cell division, moving them away from growth factors.  As they move away, the cells are less prone to division, become more differentiated, and eventually die
Figure 7.25 - Mutations in Apc case beta-catenin to escape ubiquitylation and thus drive cell growth and division

enterocytes
crypts

Section 7.12 - Von Hippel-Lindau disease: pVHL modulates the hypoxic response

Figure 7-28 - pVHL serves to degrade HIF-alpha under normative oxygen conditions.  HIF-alpha is one of a two-part transciption factor for proteins related to angiogenesis and erythropoiesis
Blood vessel growth + Cancer --> Section 13.6
Figure 7-29 - oxidation of a proline reside on HIF-alpha allows it to bind to the pVHL complex which leads to polyubiquitylation and degredation in the proteosome

hemanioblastomas
normaxia
hypoxia
angiogenesis
erythropoiesis