ICL 8.1: Molecular Basis of Cancer/Cancer Cell Signaling

Question 1

what is Pten?

Answer 1

a tumor suppressor gene

Question 2

how are Pten and p53 levels effected in prostate cancer?

Answer 2

up to 70% primary prostate tumors lose one Pten allele and retain the other copy

p53 is found completely lost or mutated almost exclusively in advance prostate cancer

loss or mutation of p53 has NOTHING to do with the initiation of prostate cancer

p53 is what notices that there’s DNA damage - with one Pten mutation the p53 doesn’t notice that there’s a problem but when there’s two Pten alleles missing the p53 notices

the worst is when you’re missing both Pten alleles and there’s a p53 mutation because then you can’t fix the DNA

Question 3

mechanistically, how does p53 function to suppress tumorigenesis?

Answer 3

p53 inhibits tumorigenesis by regulating expression of other genes

Question 4

what chromosome is Pten located on?

Answer 4

chromsome 10q23.3

Question 5

what is Cowden’s disease?

Answer 5

loss of function of Pten

Question 6

what does Pten do?

Answer 6

Pten reverses the phosphorylation of phospholipid by an enzyme called P13K

so Pten is a P1P3 phosphatase

Pten suppresses tumorigenesis by antagonizing the P13K oncogene

Question 7

how are Akt and Pten connected?

Answer 7

P1P3 is a phospholipid that the PH domain of Akt/PKB can bind to when P1P3 is triple phosphorylated

after Akt binds to P1P3 it gets doubly phosphorylated by PDK1 and PDK2 which activates Akt

Akt then phosphorylates and activates cell proliferation and size growth

Pten is a phosphatase which removes one of the phosphates on P1P3 to P1P2 so that Akt/PKB can’t bind

Question 8

what are the major substrates of AKT?

Answer 8

BAD pro-apoptotic protein

mTOR ser/thr kinase

GSK-3b ser/thr kinase

FOXO transcription factor

Question 9

why do invasive prostate cancers not select for complete loss of both Pten alleles?

Answer 9

loss of one copy of Pten is sufficient to accelerate prostate cancer tumorigenesis

AND

Loss of both Pten alleles confers an disadvantage on prostate cancer cell proliferation

Question 10

what is the Knudson paradigm of TSG inactivation?

Answer 10

The Knudson paradigm of tumor suppressor gene inactivation postulates that mutant alleles of TSGs are recessive at the cellular level

Cells that are heterozygous for a TSG should be phenotypically normal

However, for some TSGs presence of one copy is not sufficient to exert an anti-tumorigenic effect

Question 11

what is the two-hit model of tumorigenesis?

Answer 11

both alleles of a tumor suppressor gene (TSG) must be inactivated to trigger tumor formation.

Question 12

what is the haploinsufficiency model of tumorigenesis?

Answer 12

the gene-dosage defect caused by the expression of only one functional allele contributes to tumor formation either by conferring a selective advantage on the tumor cells (gatekeeper genes) or by causing genetic instability (caretaker genes)

haploinsufficiency may not result directly in a specific cellular phenotype

in both haploinsufficient scenarios, additional tumor-promoting events such as oncogenic mutations, loss of other tumor suppressor genes, or epigenetic changes will be necessary to uncover the haploinsufficiency of the original tumor suppressor gene

Question 13

which genes are haploinsufficient tumor suppressor genes?

Answer 13

AML1/CBFA2

Cdh1

Dmp1

Lkb1

NF1

p27

Ptch

Pten

Atm

Blm

Fen1

p53

Question 14

what does complete Pten inactivation in the prostate cause?

Answer 14

complete Pten inactivation in prostate induces non-lethal invasive prostate cancer after long latency

Question 15

Why the p53 is only lost in advanced prostate cancer?

Answer 15

?

Question 16

what triggers deadly invasive prostate cancer?

Answer 16

combined inactivation of both Pten and p53

Question 17

what is senescence?

Answer 17

a surveillance program guard against activation of oncogenes due to loss of TSG Pten in prostate epithelial cells

when Pten is eliminated, p19 is increased which leads to an increase in p53 which causes senescence and stops cell proliferation

if there’s no p53 then the cell just keeps on proliferating and leads to CaP initiation