Download Bmi-1 in Cancer

Bmi-1 in Cancer
Cancer genetics
2012/04/16
20128085 전종철
Contents
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Introduction
Functions of Bmi-1 in cancer
Mechanisms of Bmi-1 action
Current studies of Bmi-1
INTRODUCTION
What is the Bmi-1
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B cell-specific Mo-MLV integration site 1 (1991)
Human chromosome 10p11.23
36.9-kDa nuclear protein
The polycomb group protien
RING finger domain in its N-terminal end and a central helixturn-helix-turn-helix-turn motif(H-T-H-T)
Ginjala, V., et al., Molecular and Cellular Biology, 2011.
Li, Z., et al., Journal of Biological Chemistry, 2006.
Polycomb group protein
• The polycomb group(PcG) protiens are epigenetic
chromatin modifiers involved in cancer development
and also in the maintenance of embryonic and adult
stem cells
Bracken, A.P. and K. Helin,. Nature Reviews Cancer, 2009.
Functions of the Bmi-1
• Oncogenic activities
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Silencing tumor suppressor genes
Protection of cells from apoptosis
Promote EMT pathway
Induce telomerase activity
• Self-renewal, Proliferation and Differentiation
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Maintain self-renewal property
Hox gene silencing
Developmental regulators and differentiation factors
(TIMP-3, HHIP, INHBA)
• DNA damage protection
FUNCTIONS OF BMI1 IN CANCER
Silencing of
tumor suppressor genes(TSG)
Hedgehog
SALL4
Myc
……
RING-1
p19ARF
Bmi-1
Mel18
p16INK4a
Rb
E2F
Cdk4, 6
p16INK4a
P
Cyclin D
Rb
E2F
Bmi-1
G1 phase
p19ARF
Mdm2
stabilizing
S phase
Cell cycle
arrest
p53
G2/M
Regulation of BMI1 expression
and downstream signaling pathways
Cao, L., et al., Journal of Cellular Biochemistry, 2011.
Bmi1 affects
proliferation and apoptosis
OA : okadaic acid
TPA: 2-O-tetradecanoylphorbol-13-acetate
Lee, K., et al., Journal of Investigative Dermatology, 2007.
MECHANISMS OF BMI1 ACTION
PcG recruitment and displacement
*CTTF: cell fate transcription factor
Bracken, A.P. and K. Helin,. Nature Reviews Cancer, 2009.
Bmi-1 plays a role in H2A ubiquitination
Cao, R., Y. Tsukada, and Y. Zhang, Molecular cell, 2005.
Bmi-1 plays a key role in
regulation of the Ink4a/Arf locus
Dhawan, S., S.I. Tschen, and A. Bhushan, Genes & development, 2009.
Scheme of the Bmi-1 action
PRC1 binds to
H3K27
methylation site
Bmi1 and other
proteins perform
Repression of
Occurrence
ubiquitination in
TSGs
of the cancer
H2A
CURRENT STUDIES OF BMI1
DNA damage specific localization
of the Bmi-1
Ginjala, V., et al., Molecular and Cellular Biology, 2011.
Protection against oxidative and
DNA damage stresses
Ginjala, V., et al., Molecular and Cellular Biology, 2011.
Bmi-1 is a drug target
• HDAC inhibitors:
butyrate and valproic acid
• Inhibit the Bmi-1 expression:
siRNA and Artemisinin
• Post-transcriptional regulation:
MAPKAP kinase or Akt inhibitors
Reference
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Jiang, L., J. Li, and L. Song, Bmi-1, stem cells and cancer. Acta biochimica et biophysica
Sinica, 2009. 41(7): p. 527-534.
Valk-Lingbeek, M.E., S.W.M. Bruggeman, and M. van Lohuizen, Stem cells and cancer: the
polycomb connection. Cell, 2004. 118(4): p. 409-418.
Li, Z., et al., Structure of a Bmi-1-Ring1B polycomb group ubiquitin ligase complex.
Journal of Biological Chemistry, 2006. 281(29): p. 20643.
Ginjala, V., et al., BMI1 is recruited to DNA breaks and contributes to DNA damageinduced H2A ubiquitination and repair. Molecular and Cellular Biology, 2011. 31(10): p.
1972-1982.
Bracken, A.P. and K. Helin, Polycomb group proteins: navigators of lineage pathways led
astray in cancer. Nature Reviews Cancer, 2009. 9(11): p. 773-784.
Lee, K., et al., Expression of Bmi-1 in epidermis enhances cell survival by altering cell
cycle regulatory protein expression and inhibiting apoptosis. Journal of Investigative
Dermatology, 2007. 128(1): p. 9-17.
Dhawan, S., S.I. Tschen, and A. Bhushan, Bmi-1 regulates the Ink4a/Arf locus to control
pancreatic β-cell proliferation. Genes & development, 2009. 23(8): p. 906-911.
Cao, L., et al., BMI1 as a novel target for drug discovery in cancer. Journal of Cellular
Biochemistry, 2011. 112(10): p. 2729-2741.
Cao, R., Y. Tsukada, and Y. Zhang, Role of Bmi-1 and Ring1A in H2A ubiquitylation and
Hox gene silencing. Molecular cell, 2005. 20(6): p. 845-854.
Implicated in the self-renewal of
multiple stem cells
Ex) hematopoietic stem cell
Cell 130, 403-404 (2007)