This document discusses the intrinsic pathway of apoptosis, mediated by the mitochondria and involving the Bcl-2 family of proteins. It highlights the role of p53 as both a transcription factor and its transcription-independent regulation of apoptosis, and addresses mutations affecting the regulators of this pathway. Key references are provided for further reading on the molecular biology of cancer and apoptosis mechanisms.

1. The intrinsic pathway:
mediated by the
mitochondria
Presented by: Fatemeh Gila
RIP
CELL

2. 4 exon
18q21.33
Bcl-2 family
2

3. Bcl-2
Bim
Bax
Bad
Bak
Boo
Mcl-1
Bcl-x/w
Bcl-2
Members of the Bcl-2 family
Anti-apoptotic
members
Pro-apoptotic members
oncogenes
Tumor suppressor
3

4. Anti-
apoptotic
members
Pro-apoptotic
members
It’s a seesaw
4

5. AIF
Bcl-2
Cytochrome c
SMAC/DIABLO
Pro-caspase9
APAF-1
IAP
Normal cell
5

6. + +
SMAC/DIABLO
IAP
Cyt.c APAF-1
Pro-caspase9
Apoptosome
apoptosise
6

7. + Pro-caspase3
Apoptosome
caspase9
APAF-1
Cytochrome c
Active caspase3
Apoptosome
complex
7

8. Cross-talk between extrinsic and intrinsic
pathways
8

9. p53 as a transcription
factor
p53
Induce:
Fas re
Bak
Bax
Repress:
IAP
Bcl-2
Bcl-x
9

10. p53 can exert transcription-independent regulation of apoptosis
10

11. p53 and apoptosis
11

12. P53 and PUMA duo
12

13. Mutations affecting regulators of the intrinsic
pathway
13

14. Mutations in the p53
gene
mutations in the upstream genes of
p53
mutations in downstream targets ofp53
mutations in MDM2
components
induction of inhibitors of
apoptosis
Mutation in the Downstream molecules of
mitochondrial apoptosis factors
Abnormal methylation and LOF for p73
alternative splicing
epigenetic inactivation
Mutations

15. EXAMPLE
MDM
2
Bax
p73
XIAP
15

16. References:
-Molecularvbiology of cancer, Lauren
-Speidel D. Transcription-independent p53 apoptosis: an alternative route to death. Trends in cell biology. 2010
Jan 1;20(1):14-24.
- Vikhreva P, Melino G, Amelio I. p73 alternative splicing: exploring a biological role for the C-terminal isoforms.
Journal of molecular biology. 2018 Jun 22;430(13):1829-38.
16

17. Thanks for your
attention