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Copy of PhD Defence 20062013

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Rajesh Vyas

on 9 June 2014

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Transcript of Copy of PhD Defence 20062013

Studying the physiological relevance of
putative modifiers of the p53 tumour suppressor pathway using mouse as a model system

Cop1 Deficiency does not affect p53 Levels
Introduction
In almost
50%
of human malignancies
p53
is
p53
In Many of the remainders p53 pathway is impaired through its negative regulation
Genetic studies have identified key modifiers of p53
reviewed in Marine and Lozano CDD, 2010
Search for novel modifiers of p53
Biochemical Studies
In vivo relevance
p53
Cop1
Rnf4
Tctp
Cop1
Rnf4
Tctp
Summary
We are E3 Ubiquitin ligase
Cop1 deficiency
does
not
effect
p53 transcriptional activity
An inverse co-relation exist between Cop1 and cJun protein levels in human prostate cancers
Cop1
c-Jun
Studying the physiological relevance of
putative modifiers of the p53 tumour suppressor pathway
using mouse as a model system
L
aboratory of
M
olecular
C
ancer
B
iology
VIB-K.U. Leuven
Belgium
Rajesh Vyas
Generation of an Allelic series of Rnf4
Rnf4 deficient mouse embryonic fibroblasts
exhibit growth disadvantage

RNF4 deficiency leads to increased IR-induced DNA damage
p53 responds to diverse stresses
Bieging and Attardi, Cell, 2011
Ubiquitin Proteosome Pathway
Cancer
p53
Rnf4
Cop1
Ablation of Cop1 leads to embryonic lethality
which is not rescued by p53 loss

Rnf4 is required for enforcing the radiation-induced G2/M

DNA damage checkpoint in MEFs
Decreased Rnf4 expression leads to increased
sensitivity to IR-induced apoptosis
DNA Damage Signaling is sustained in Rnf4 deficient conditions
C
A
B
RNF4 is recruited to sites of DNA damage

Recruitment of Rnf4 on DNA Damage site is SIM-dependent
Rnf4 is required for HR & NHEJ
Rnf4 is required for the recruitment of
Rad51 to IR-induced DNA damage sites
Impaired spermatogenesis in Rnf4-hypomorphic mice
Tctp haploinsufficiency increases the amount of p53
A
B
A
B
Tctp haploinsufficiency enhances susceptibility to P53-dependent apoptosis
Tctp haploinsufficiency enhances susceptibility to P53-dependent apoptosis
p53
Tctp
Rnf4
Cop1
Conclusions
Cop1, p53 Stability and Human Malignancies

p53 Stability is not effected by Cop1 Deficiency.

No biochemical or genetic evidence in support of a role for Cop1 in the regulation of p53 stability or activity. these data strongly argue against the use of Cop1-inhibitory drugs for cancer therapy.

Our findings argue that COP1 loss of function contributes to the development of human malignancies, at least partly through up-regulation of c-Jun levels and activity.
Cop1 in etiology of cancer ?
Cop1 and regulation of p53 Stability ?
Cop1, c-Jun and Human Malignancies ?
Conclusions
p53
Tctp
Rnf4
Cop1
Cop1, p53 Stability and Human Malignancies

p53 Stability is not effected by Cop1 Deficiency.

No biochemical or genetic evidence in support of a role for Cop1 in the regulation of p53 stability or activity. these data strongly argue against the use of Cop1-inhibitory drugs for cancer therapy.

Our findings argue that COP1 loss of function contributes to the development of human malignancies, at least partly through up-regulation of c-Jun levels and activity.
RNF4 is required for DNA double-strand break repair in vivo
Rnf4-deficiency leads to increased sensitivity to DNA damage
Rnf4-deficiency leads to increased IR-induced DNA damage and sustained DNA damage signaling
RNF4 is recruited to IR-induced DNA damage foci
SUMOylated MDC1 and SUMOylated BRCA1 are regulated by RNF4
RNF4 deficiency affects both HR and NHEJ
Rnf4 is required for recruitment of Rad51 to IR-induced DNA damage sites

Impaired spermatogenesis in Rnf4-hypomorphic mice
Conclusions
p53
Tctp
Rnf4
Cop1
Cop1, p53 Stability and Human Malignancies

p53 Stability is not effected by Cop1 Deficiency.

No biochemical or genetic evidence in support of a role for Cop1 in the regulation of p53 stability or activity. these data strongly argue against the use of Cop1-inhibitory drugs for cancer therapy.

Our findings argue that COP1 loss of function contributes to the development of human malignancies, at least partly through up-regulation of c-Jun levels and activity.
RNF4 is required for DNA double-strand break repair in vivo
Rnf4-deficiency leads to increased sensitivity to DNA damage
Rnf4-deficiency leads to increased IR-induced DNA damage and sustained DNA damage signaling
RNF4 is recruited to IR-induced DNA damage foci
SUMOylated MDC1 and SUMOylated BRCA1 are regulated by RNF4
RNF4 deficiency affects both HR and NHEJ
Rnf4 is required for recruitment of Rad51 to IR-induced DNA damage sites

Impaired spermatogenesis in Rnf4-hypomorphic mice
Genetic link between Tctp haploinsufficiency and P53
Tctp Haploinsufficiency results in increased p53 levels in mice
Tctp Haploinsufficiency leads to increased sensitivity to basal and radiation-induced apoptosis.

This augmented sensitivity was not observed on a p53-null background; an observation that provides direct genetic evidence in support of role of Tctp in regulating p53-mediated apoptosis
Summary
p53
Tctp
Rnf4
Cop1
Cop1, p53 Stability and Human Malignancies

p53 Stability is not effected by Cop1 Deficiency.

No biochemical or genetic evidence in support of a role for Cop1 in the regulation of p53 stability or activity. these data strongly argue against the use of Cop1-inhibitory drugs for cancer therapy.

Our findings argue that COP1 loss of function contributes to the development of human malignancies, at least partly through up-regulation of c-Jun levels and activity.
RNF4 is required for DNA double-strand break repair in vivo
Rnf4-deficiency leads to increased sensitivity to DNA damage
Rnf4-deficiency leads to increased IR-induced DNA damage and sustained DNA damage signaling
RNF4 is recruited to IR-induced DNA damage foci
SUMOylated MDC1 and SUMOylated BRCA1 are regulated by RNF4
RNF4 deficiency affects both HR and NHEJ
Rnf4 is required for recruitment of Rad51 to IR-induced DNA damage sites

Impaired spermatogenesis in Rnf4-hypomorphic mice
Genetic link between Tctp haploinsufficiency and P53
Tctp Haploinsufficiency results in increased p53 levels in mice
Tctp Haploinsufficiency leads to increased sensitivity to basal and radiation-induced apoptosis.

This augmented sensitivity was not observed on a p53-null background; an observation that provides direct genetic evidence in support of role of Tctp in regulating p53-mediated apoptosis
c-Jun
Rnf4
: link to
P53
&
DNA Damage
repair
?
!?
Tctp
Execution of Antiapototic activities- link to p53 stability!!?
Fredric Clermont
Aart Jochemson
Ramesh Kumar
Alfred Veregaal
Enrico Radaelli
Anna Sablina
Peter Kalev
Cedric Blanpain
Odessa
Greet
Domenico Migliorini
Enrico Radaelli
Odessa
Greet


Adam Telerman
Robert Amson
Jessika W.
Odessa
greet

Prof. Chris Marine
All Present and past LMCB Members
Thanks
& Acknowledgements
Decreased survival of Tctp +/- mice upon whole body ir-radiation
Rad51
y-H2AX
M
e
r
g
e
RNF4 +/+
RNF4 h/h
Full transcript