p53 role in HPV tumorogenesis

how

binds to and mediates the degradation of p53

1. HPV E6 pro
catalytic subunit of telomerase
stimulates the expression of TERT
-> immortalization of cell

binding RB protein allows E2F transcription factor to

2. HPV E7 pro
increased CDK4 and cyclinD binding inhibit p21 promote cell cycle progression by

in all cells of body

inherited autosomal dominant Help to repair DNA inhibition of uncontrolled mutations

Li Fraumeni Syndrome and p53
alteration of the p53
can be
de novo mutations early in embryogenesis Control if the cells attachment to other cells or the ECM is if cells lose their attachment to basal
or in one of the parent's germ cells are attached essential for cell growth and survival lamina -> cell death aka ANOIKIS
function encode x pro that
LOW common tumor = invasive EXTERNAL - Control signal
cell cycle INHIBITION
> eg skin cancer/ MELANOMA transduction pathways

1.Breast cancer (25% early onset) what Activate APOPTOSIS if cell homeostasis is altered

2.Soft tissue sarcomas Familial Adenomatous Polyposis

(20%, with bone 15%) types rare cancer predisposition APC
risk of develop INTERNAL INVASIVE CANCER interact with beta-catenin in Wnt signaling pathway
HIGH common tumors are 5 hereditary disorder
3.Brain tumors (glioblastomas 15%)
Retinoblastoma
4.Leukemia and lymphoma RB pro
cell cycle brake, bind E2 transcription factor complex
5.Adrenocortical gland tumors
neurofibromatosis type 1
50% at 30y.o, 90% at 70 y.o NF1
most imp
downregulate Ras pro
Tumor Suppressor Genes Li Fraumeni Syndrome
act as transcriptional factor
what TP53/ P53 transcriptional factor, cell cycle
located on chromosome 17p13 arrest or apoptosis

difference of AA only a base exchange Familial Adenoma

P14, P16
p53 function no more functional CDK4 inhibitor

missense point mutation (86%)

mild effect, no much problems

they can bind tyo DNA bc you loose only 2 of the 4 subunits most problematic
acts in a DOMINANT features
after a point mutation
FASHION!

1. You lack only one p53 allel (p53+ wild-type/p53- mutant)

tumor bc p53 act as a TETRAMER 3 types of mutations Most act in a “Dominant”Fashion -> both
2. You you loose the second allel (p53-/p53-)
Copies (Alleles) need to be Inactivated
they cannot bind the DNA you loose all 4 subunit

degradation of pro premature stop codon nonsense mutations (5%)

mutated
RB1
deletions or insertions (8%)
CDK4
directly p53-/p53- -> directly mainly in APC and
why low n° of them? frameshift mutation in genes that regulate
loss of p53 function BRCA1, not in p53 mutations genes encoding cyclin D pro
the phosphorylation of RB
in 75% cancers genes encoding CDKN2A (p16)
Lecture 12 TGF-beta

neoplastic proliferation
what
in codons 245, 248 and 273 of retinal cells
(SV40T binding, see the black lines) similar to sporadic cancers Germline Mutations affects one or both eyes
if there is a mutation CANNOT bind are in the sequence specifific x preferentially occur in HOTSPOT REGIONS ONCOLOGY
the DNA anymore -> no functional DNA binding domain inherited in autosomal dominance
manner (so act as dominant)
is an example of
40% cases
cellularly it is a autosomal incomplete penentrance
most mutations occur in exons 4,5,6,7,8
recessive trait
is present in LOW concentration in only one additional RB mutation is required
normally 9/10 cases have disease
cells bc of its instability -> degraded for complete loss of RB function
cell cycle inhibitor p21
1. Probability of a single mutation is low -> but
if damage is low
DNA repair pro (GADD45) after 1th mutation = errors in DNA amplification
what
senescence induction pro 2. During DNA replication the DNAPol -> DNApol shuffle gentic material btw
“jumps”from one to the other chromosome chromosomes leading to the 2th mutation
Bcl-2 its stability increase and its
encode gene x if isn't mutated
concentration in cells INCREASE
APAF1 (apoptosome) if damage is ti high
pro-apoptotic pro 1. Btw one of chromatid arms carrying the wild- one is maternal and
DR5 type Rb allele and one carrying the mutant allele the other paternal

CD95/ FAS 2. After replication both alleles

become homozygous
2 possible outcomes TP53 (p53) suppressor could be mutated
RB1 suppressor gene: Retinoblastoma Mitotic Recombination contribute to Rb inactivation
gene "the angel of cells"
LOSS OF HETEROGENICITY/
HETEROZIGOSITY (L OH)

FAMILIAL all somatic cells inherit one mutated

one aploid die
NON FUNCTIONAL if is mutated mutations of RB locus retinoblastoma copy of RB gene from a carrier parent
2 types via the
on chrom. 13q14 if removal of the non mutant allele ->
one tetraploid
remain with 2 mutant alleles -> LOH
3 ways
development of # tumors Error during the distribution of Chromosoms during mitosis

if stress situation
hypoxia

DNA damage

activated oncogene (growth stress)

ribonucleotide function
depletion (no ATP)

cell death
sense it and induce
cell senescence
Partial deletions of chromosoms (e.g., after
type of stress situa double strand breaks

TELOMERES EROSION affects only one eyes

60% cases no genetic influence

all somatic cells have you need 2 random mutation in the tumor-
no mutation founding retinal cell to have loss of RB function
SPORADIC
enzyme TELOMERASE can retinoblastoma
IMMORTALIZE cancer cells

1.p53 stimulates the expression of MDM2

by ubiquination of p53 -> 2. MDM2 induces p53 degradation in the nucleus/ cytoplasm, blocks its normally
proteasome destruction transcriptional activity and promotes its nuclear export

pention of their interaction

phosphorylation of p53 and MDM2 if DNA damaged
and stabilizing p53

induction of ARF pro -> sequesters

NO degradation of p53 if activated oncogenes
MDM2 into the nucleolus

mediation of nuclear import of MDM2 via

if survival signals
Akt activation -> destabilization of p53 regulation: p53 and Mdm2 autoregulatory loop

inhibition of Mdm2 -> Mdm2 is usually it has NO target therapy ->

p53 activation preferred to much dangerous

treatment