Xin Lu (Ludwig Institute for Cancer Research, United Kingdom)
“p53, a Key Regulator of Genomic Stability in Cancer”
- Discovery of p53: 1979 about the same time “tumor antigen” by Lloyd and Old, PNAS.
- Binding partner of large T antigen of SV40 (A Larid and David Lane)
- p53 mutation in 30–40% BL, why only 9 % in NPC
- A review paper in 2008 (Murray-Zmijewski et al., Nat Rev Mol Cell Biol, 2008)
- P53: a guardian of cellular plasticity (ability to change for one state to another)
- KLF4/SOX2/OCT4/MYC → iPS. In this setting, get rid of p53 (or p16) enhances iPS.
- Over 80% melanoma cell harbor structurally wild type but functionally defective p53, why?
- Synthetic suppression (B-RAF 50%, p53 <20 150="" been="" cellular="" have="" identified="" interact="" li="" over="" p53="" protein="" to="" with="">
- ASPP (ankyrin-repeat, (Zta also has this motif?), SH3-domain)
- ASPP1, ASPP2, iASPP
- ASPP1 and 2 (陰, which activate p53/p63/p73)
- iASPP (陽, which inactivate p53/p63/p73)
- JNJ-7706621 CCNB/CDK1 inhibitor can be used as an iASPP inhibitor since iASPP inactivates p53 via phosphrylating CCNB1/CDK1. (+Nutlin to suppress MDM2)
- RaDAR (RanGDP/Ankyrin repeat binding) code (Lu et al., Cell, 2014)
- Hyrdophobic 13th residue (Notch, Ankyrin 1, 2, NF-KB etc)
- Altering RaDAR code can change cellular location of ARPs.
- CDKN2A (p16) M53I & R87P both are 13th residue of ankyrin repeats
- ARPs are enriched in the nucleus and many RaDAR code containing ARPs are regulators of NFKB & p53
- Many cytoplasmic-nuclear shuttling proteins cannot bind DNA but are able to influence transcript (MRTF → binds actin in the cytoplasm, b-catenin, ASPP, YAP etc) (Lu et al., Nat Rev Mol Cell Biol, 2016)
- 好像聽到她提到 Zta 有ankyrin motif, CYLD/BCL3/NFKB blablabla
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From Ming-Han
- P53 problem in 70% of BL; most of NPC cell line but only 9% of the PRIMARY NPC TUMOR. It seems p53 functions totally different in different cell line.
- ie: P53+53bp1: DNA repair
- P53+53BP2; p53+BCLXL, P53+ASSP+DNA…. many different functions.
- @By ips (KLH4, Sox2, myc, Oct4); we found P53 or p16 can block the differentiation of ups cells.
- @RaDarCode (interestingly the protein that regulate p53 are more often by using this way than NLS)
- Why some proteins has no NLS but can anyway move to the nucleus?
- -example: RanGDP/Ankynin repeats binding code.
- NLS binding to importin-> RanGTP to GDP-> bring NLSprotein to nucleus -> NES code move outside.
- Example: EBV CYLD: (CYLD+BCL3) to nucleus that can elevate p53 level But if CYLD mutant then can’t move to nucleus; even if p53 is intact but similar to p53 mutation.
- 聽到有點恍神這個