Senescence

Senescence
Cellular Organismal
Normal Senescent Young Old
RANJEET SINGH; mahlaranjeet@gmail.com

Why senescence is important?
Ref: Frontiers in
Bioscience 14,
4044-4057,
January 1, 2009

Molecular players of senescence
Ref: Chen et al
2006

Terminologies in senescence
1. Senescence: derived from Latin word senex, meaning old man or old
age.
2. Cellular senescence/Replicative senescence/Hayflick limit: Due to
telomerase shortening cells cease to divide in culture.
3. Crisis: State characterized by extensive genomic instability and cell
death.
4. OIS: Activation of oncogenes, DNA damage, ROS and cell fusion
(independent of telomerase shortening).
5. Agonescent: Epithelial cells arrest with obvious signs of genomic
instability . •
1. Senescence: derived from Latin word senex, meaning old man or old
age.
2. Cellular senescence/Replicative senescence/Hayflick limit: Due to
telomerase shortening cells cease to divide in culture.
3. Crisis: State characterized by extensive genomic instability and cell
death.
4. OIS: Activation of oncogenes, DNA damage, ROS and cell fusion
(independent of telomerase shortening).
5. Agonescent: Epithelial cells arrest with obvious signs of genomic
instability . •
Ref: Judith Campisi et al 2007

What is the relation among p53 and PTEN
Trotman et al 2003; Atsuko Nakanishi et al 2014

Generation of prostate specific knock out mice

What is the effect of p53 and PTEN loss on prostate tumor ?
WT P53 K/O Double K/OPTEN K/O
Histology
MRI
LG-PIN HG-PIN
LG-PIN HG-PIN
P53 loss does not initiate tumor
PTEN loss initiate prostate tumor
p53 loss aggravates tumor (only when PTEN is already lost)
Weight & Size
LG-PIN HG-PIN

What is the effect of p53 and PTEN loss on survival?
Tumor invasiveness Effect on survival
P53 loss in PTEN null background induces tumor invasiveness.
 P53 loss in PTEN null background decrease survival of mice.

Role of PTEN in senescence and proliferation ?
PTEN and MEF proliferation PTEN and MEF proliferation
PTEN heterozygosity induce proliferation.
 Loss of heterozygosity induces senescence

PTEN loss; P-Akt and p21
PTEN –P53 depletion and cell proliferation ?
PTEN-P53 loss and proliferation
PTEN loss induces pAkt (promotes proliferation)
P53 loss after PTEN loss induces proliferation
 P53 loss after PTEN loss restrict senescence

Impact of PTEN loss on stability of P53 ?
PTEN loss and p53 stability PTEN loss and p19
PTEN loss increase p53 half life
PTEN loss induces pAkt that induces
senescence
PTEN loss results in ARF induction
PTEN loss pAkt and senescence

Impact of PTEN loss on senescence pathway?
Loss of PTEN induces senescence
PTEN loss induces p53
Loss of PTEN induces senescence
PTEN loss induces senescence through p19Arf →p53 → p21
PTEN loss induces p53

Impact of PTEN loss on senescence pathway?
PTEN loss induces p53 functions
Loss of p53 is crucial for cancer progression

• Acute loss of Pten does not result in decreased, but increased, p53
levels and function.
• Loss of Trp53 has no effect on Pten expression in vitro and in prostatic
epithelium, whereas in combination with loss of Pten a lethal
acceleration of prostate cancer is observed.
• Regarding the Pten–p53 network, data lend no support to a ‘two-in-
one’ hit model of tumorigenesis, but as both genes need to be ablated
for maximal disease progression they suggest a ‘one-by-one’ hit model
for the genetic interaction of these major tumour suppressor genes.
• The fact that acute homozygous (not heterozygous) loss of Pten
triggers a p53-dependent cellular senescence programme in vivo
provides a plausible explanation for why human prostate cancer at
presentation does not select for complete loss of PTEN and thus
highlights the relevance of PTEN haploinsufficiency for prostate cancer
initiation.
• Complete p53 inactivation alone has no phenotypic consequences in
prostate could explain why loss of p53 is preferentially selected for in
advanced prostate cancer where in addition it could allow the tumour
to reach maximal proliferation through PTEN loss of heterozygosity.
Summary
• Acute loss of Pten does not result in decreased, but increased, p53
levels and function.
• Loss of Trp53 has no effect on Pten expression in vitro and in prostatic
epithelium, whereas in combination with loss of Pten a lethal
acceleration of prostate cancer is observed.
• Regarding the Pten–p53 network, data lend no support to a ‘two-in-
one’ hit model of tumorigenesis, but as both genes need to be ablated
for maximal disease progression they suggest a ‘one-by-one’ hit model
for the genetic interaction of these major tumour suppressor genes.
• The fact that acute homozygous (not heterozygous) loss of Pten
triggers a p53-dependent cellular senescence programme in vivo
provides a plausible explanation for why human prostate cancer at
presentation does not select for complete loss of PTEN and thus
highlights the relevance of PTEN haploinsufficiency for prostate cancer
initiation.
• Complete p53 inactivation alone has no phenotypic consequences in
prostate could explain why loss of p53 is preferentially selected for in
advanced prostate cancer where in addition it could allow the tumour
to reach maximal proliferation through PTEN loss of heterozygosity.

Senescence

Recommended

Recommended

More Related Content

What's hot

What's hot (20)

Similar to Senescence

Similar to Senescence (20)

Recently uploaded

Recently uploaded (20)

Senescence