TP53 - The Guardian of the cell by K.A. MacManus https://padlet.com/kamacmanus/rzlbwofp9f5t Oncology - Katie, Odile and Hassan en-us 2020-03-27 12:29:04 UTC 2024-06-08 03:26:03 UTC hello@padlet.com Clinical Relevance odeleastar https://padlet.com/kamacmanus/rzlbwofp9f5t/wish/486671557 TP53 is the most frequently inactivated gene in cancer.
It is mutated in:
  • 96% of ovarian serous carcinomas
  • 85% of small cell lung cancers
  • 75% of pancreatic cancers
  • 60% of head and neck squamous cell carcinomas 
  • 54% of invasive breast carcinomas. 
These mutations can often lead to a gain of function oncogenic phenotype, which are associated with poor prognosis. Additionally, over expression of inhibitors of p53 (i.e. MDM2) can also be used for screening and prognosis. 
]]> 2020-04-01 13:40:42 UTC https://padlet.com/kamacmanus/rzlbwofp9f5t/wish/486671557 Restoring WT p53 function: odeleastar https://padlet.com/kamacmanus/rzlbwofp9f5t/wish/486676821 With the aid of computational prediction of p53 structural models, an array of small molecules have been developed which are designed to attach to mutant p53 at specific sites to induce refolding of the mutated protein into a functional p53 structure which is able to bind to DNA.
Preclinical studies showed that WTp53 in p53 null or mutant tumour cells was enough to slow or regress the tumour progression. 
One particular molecule under study is APR-246, which was shown to effectively lead to the apoptosis of tumour cells in multiple cancers. ]]> 2020-04-01 13:42:30 UTC https://padlet.com/kamacmanus/rzlbwofp9f5t/wish/486676821 Fixing mutant p53 activity odeleastar https://padlet.com/kamacmanus/rzlbwofp9f5t/wish/486683466 Mutant p53 often binds to and inhibits p63 and p73, obstructing their tumour suppressive function.
 This has led to approaches inhibiting or disassembling mutp53/p63 and mutp53/p63 complexes.
Short peptide aptamers were also able to specifically interfere with mutant p53 and induce cell death in mutant p53 cells. A library of peptides that interact with mutp53 and lead to the apoptosis of mutp53 cells has been found. As these are peptides of proteins that interact with normal p53 it is hypothesized that these peptides can bind and stabilize to mutp53 when it transiently exhibits wt conformation. These are promising therapies as they specifically target mutp53 and exclude an effect on wt p53. Other potential therapies use  dietary components capsaicin and cruciferous-vegetable-derived phenethyl isothiocyanate (PEITC). Another target may be stem cell proliferation factor FOXH1.

]]> 2020-04-01 13:45:07 UTC https://padlet.com/kamacmanus/rzlbwofp9f5t/wish/486683466 Targeting Genomic Instability of mutp53 odeleastar https://padlet.com/kamacmanus/rzlbwofp9f5t/wish/486712180 Some mutp53 proteins has been shown to interact with and inhibit DNA repair proteins such as the MRE11, BRCA1 and RAD17 proteins responsible for responding to double strand breaks. Similar approaches to the FDA approved PARP inhibition in ovarian cancer have been proposed. This is based on synthetic lethality. (fig a)

When BRCA1 is already downregulated, cells with not enough BRCA1 will die as there is no way for them to fix double strand breaks. 
MuTP53 proteins have also been shown to disrupt the architecture of telomeres. ]]> 2020-04-01 13:55:22 UTC https://padlet.com/kamacmanus/rzlbwofp9f5t/wish/486712180 Targeting WEE1 protein kinase odeleastar https://padlet.com/kamacmanus/rzlbwofp9f5t/wish/486718690 WEE1 is a checkpoint inhibitor responsible for preventing mitosis in the presence of DNA damage. WEE1 has been indicated to aid the survival of mutp53 and its inhibition has led to the selective apoptosis of mutp53 cells. 

This inhibition is able to be selective against mutp53 cells because WEE1 is responsible for cell cycle arrest in the G2 phase of the cell cycle. It has been shown that wtp53 cells arrest at the G1 phase of the cell cycle  mutp53 cells rely on DNA repair at the G2 checkpoint. This is because wtp53 would normally function as a G1 checkpoint protein (fig. b).]]> 2020-04-01 13:57:51 UTC https://padlet.com/kamacmanus/rzlbwofp9f5t/wish/486718690 Refrences odeleastar https://padlet.com/kamacmanus/rzlbwofp9f5t/wish/486753957 Blandino, G., & Di Agostino, S. (2018). New therapeutic strategies to treat human cancers expressing mutant p53 proteins. Journal of Experimental & Clinical Cancer Research, 37(1), 30.
https://jcs.biologists.org/content/123/15/2527.short
http://www.bioinformatics.org/p53/introduction.html]]> 2020-04-01 14:10:35 UTC https://padlet.com/kamacmanus/rzlbwofp9f5t/wish/486753957 Mutant TP53 and History odeleastar https://padlet.com/kamacmanus/rzlbwofp9f5t/wish/487430733 In cancer p53 becomes mutated (muTP53); the tumour suppressor functions are severely inhibited; loss-of-wild-type function mutations.
This muTP53 acts as an oncogene and is the reason that when tp53 was discovered it was believed to have been one.
cWhen it was discovered they found that the p53 protein was bound to the major oncogenic protein of SV40, this indicated to them that it was a downstream effector of the large T-antigen pathway, furthermore as muTP53 was highly expressed in many cancer, the evidence suggested that it was an oncogene.
After some research, they found out that this mutp53 gene converted a regular cell into a cancer cell.  
in 1968 they realized this was the mutated not the WT gene]]> 2020-04-01 18:32:15 UTC https://padlet.com/kamacmanus/rzlbwofp9f5t/wish/487430733 TP53 in cancer odeleastar https://padlet.com/kamacmanus/rzlbwofp9f5t/wish/487431852 This p53 gene acts almost in the opposite to how it acts in non-cancer cells. If p53 is WT– as shown in a study by Yonish-Rouach et al. 1991 the expression in cancer cells is apoptosis.

Different to most tumour suppressor mutations; most of TP53 mutations are missense. The exact pathways and mechanism remain incomplete and are to be understood, however evidence suggests that this muTP53 (mutant TP53 gene) gives the cell information and the ability to cope with the challenging conditions – due to initial WT function.
It changes, instead, with its reaction and instead coordinates adaptive responses that support cell proliferation and homeostasis to support the tumour progression.

]]> 2020-04-01 18:32:43 UTC https://padlet.com/kamacmanus/rzlbwofp9f5t/wish/487431852 !!!!DISCLAIMER!!!! hhajmohammad https://padlet.com/kamacmanus/rzlbwofp9f5t/wish/487763743 Adding exogenous p53 into the body does NOT work and causes premature aging.]]> 2020-04-01 22:11:02 UTC https://padlet.com/kamacmanus/rzlbwofp9f5t/wish/487763743 Associated Cancers hhajmohammad https://padlet.com/kamacmanus/rzlbwofp9f5t/wish/487768942 Breast Cancer
NIM Bladder Cancer
Ovarian Cancer
SC Lung Cancer
HNSCC
Bile Duct Cancer
Pancreatic Cancer
Melanoma
Colon Cancer]]> 2020-04-01 22:16:56 UTC https://padlet.com/kamacmanus/rzlbwofp9f5t/wish/487768942 This TP53 gene codes for the p53 protein; with the normal function of this gene is acting as a tumor suppressor. It regulates cell division by preventing cells from proliferating too fast- or in an uncontrolled way kamacmanus https://padlet.com/kamacmanus/rzlbwofp9f5t/wish/488072136 2020-04-02 05:34:14 UTC https://padlet.com/kamacmanus/rzlbwofp9f5t/wish/488072136 kamacmanus https://padlet.com/kamacmanus/rzlbwofp9f5t/wish/488072360 P53 is found in the nucleus cells, binds here directly to the DNA to regulate gene expression to prevent mutations of the 
DNA damage:
  •  toxic chemicals,
  •  radiation, 
  • UV rays
 p53 plays a crucial role in determining whether the DNA will be repaired; p53 will then activate other genes to fix the damage. If the DNA is beyond repair, then p53 prevents proliferation and instead signals for apoptosis. p53 also interacts directly with AP endonuclease and DNA polymerase which are involved in base excision repair.
]]> 2020-04-02 05:34:32 UTC https://padlet.com/kamacmanus/rzlbwofp9f5t/wish/488072360 kamacmanus https://padlet.com/kamacmanus/rzlbwofp9f5t/wish/488072700 2020-04-02 05:35:03 UTC https://padlet.com/kamacmanus/rzlbwofp9f5t/wish/488072700 kamacmanus https://padlet.com/kamacmanus/rzlbwofp9f5t/wish/488076932 2020-04-02 05:40:52 UTC https://padlet.com/kamacmanus/rzlbwofp9f5t/wish/488076932 kamacmanus https://padlet.com/kamacmanus/rzlbwofp9f5t/wish/488082595 2020-04-02 05:48:36 UTC https://padlet.com/kamacmanus/rzlbwofp9f5t/wish/488082595 kamacmanus https://padlet.com/kamacmanus/rzlbwofp9f5t/wish/488091701 2020-04-02 06:00:57 UTC https://padlet.com/kamacmanus/rzlbwofp9f5t/wish/488091701 muTP53 kamacmanus https://padlet.com/kamacmanus/rzlbwofp9f5t/wish/488097473 Many studies have shown that this is the most mutated gene in tumours (>50%) in the whole human genome, and >25,000 TP53 mutations have been reported to date. Most of the mutations are a single base, somatic substitution (often C to T) which leads to a new amino acid.
Li-Fraumenis syndrome is an autosomal, dominant missense of TP53 that leads to a variety of cancers at a young age.
 In almost all cases both of the copies of TP53 in the cell are mutated, one generally altered by this base substitution and the second often deleted; these findings resulted in the realization that TP53 is a tumour suppressor, not an oncogene. ]]> 2020-04-02 06:08:01 UTC https://padlet.com/kamacmanus/rzlbwofp9f5t/wish/488097473 fig a and fig b kamacmanus https://padlet.com/kamacmanus/rzlbwofp9f5t/wish/488102573 2020-04-02 06:13:25 UTC https://padlet.com/kamacmanus/rzlbwofp9f5t/wish/488102573 kamacmanus https://padlet.com/kamacmanus/rzlbwofp9f5t/wish/488141173 muTP53 oncoproteins are stable and activated in response to tumour-related stress -other than this they are generally very unstable]]> 2020-04-02 06:48:53 UTC https://padlet.com/kamacmanus/rzlbwofp9f5t/wish/488141173