A comprehensive functional analysis of TP53 mutations in human leukemia may refute a working hypothesis - primarily based on mouse studies - that missense mutations confer new cancer-causing functions to the p53 tumor suppressor protein; the new study instead suggests that these mutations exert a "dominant-negative" effect that reduces the cancer-suppressing activity of wild-type p53, the authors say.
The TP53 gene was discovered 40 years ago and it now known to be the most frequently mutated gene in human cancer. Initially, TP53 was mischaracterized as an oncogene but human genetic studies ultimately established that it encodes a tumor suppressor. But how cancer-associated mutations in TP53 alter the function of wild-type p53 has continued to be the subject of debate.
The vast majority of TP53 mutations across all cancer types are missense mutations, which can result in non-functional or dysfunctional p53. Based largely on mouse model experiments, it has been hypothesized that certain missense mutations can transform the p53 tumor suppressor into a tumor promoter via so-called oncogenic "gain of function" (GOF) effects.
To explore the functional consequences of p53 mutations, researchers performed a comprehensive analysis of TP53 mutations in human myeloid leukemia. Using CRISPR/Cas9 gene editing technology, the authors generated isogenic human leukemia cell lines featuring the most common p53 missense variants.
This isogenic analysis - as well as comprehensive mutational screening, in vivo experiments in mice and an analysis of clinical data - did not support the notion that missense mutations confer new oncogenic functions to the p53 tumor suppressor protein.
Instead, the authors discovered that the mutations confer either loss of function effects or dominant-negative effects (DNE) that reduce the tumor-supressing efficacy of wild-type p53 in human leukemia. In mice, the DNE of p53 missense variants confers a selective advantage to hematopoietic cells on DNA damage. Analysis of clinical outcomes in patients with acute myeloid leukemia showed no evidence of GOF for TP53missense mutations. Thus, a DNE is the primary unit of selection for TP53 missense mutations in myeloid malignancies.
https://science.sciencemag.org/content/365/6453/599
Type of TP53 mutations and their affect in cancer
- 2,547 views
- Added
Edited
Latest News
Wiring of the human neocortex
By newseditor
Posted 24 Apr
Abusive drugs hijack natura…
By newseditor
Posted 23 Apr
Mechanism of action of the…
By newseditor
Posted 23 Apr
Role of fat in rare neurolo…
By newseditor
Posted 23 Apr
How protein synthesis in de…
By newseditor
Posted 22 Apr
Other Top Stories
Laboratory technique recapitulates all stages of egg cell development
Read more
Babies' spatial reasoning predicts later math skills
Read more
Embryos with "heteroplasmy," or the presence of both maternal and p…
Read more
Immune cell involvement in brain development revealed!
Read more
Blood cell types emerge through internal struggles
Read more
Protocols
A programmable targeted pro…
By newseditor
Posted 23 Apr
MemPrep, a new technology f…
By newseditor
Posted 08 Apr
A tangible method to assess…
By newseditor
Posted 08 Apr
Stem cell-derived vessels-o…
By newseditor
Posted 06 Apr
Single-cell biclustering fo…
By newseditor
Posted 01 Apr
Publications
Harnessing gastrointestinal…
By newseditor
Posted 24 Apr
Sex-specific modulation of…
By newseditor
Posted 24 Apr
Exploiting pancreatic cance…
By newseditor
Posted 23 Apr
Structure of antiviral drug…
By newseditor
Posted 23 Apr
Type-I-interferon-responsiv…
By newseditor
Posted 23 Apr
Presentations
Hydrogels in Drug Delivery
By newseditor
Posted 12 Apr
Lipids
By newseditor
Posted 31 Dec
Cell biology of carbohydrat…
By newseditor
Posted 29 Nov
RNA interference (RNAi)
By newseditor
Posted 23 Oct
RNA structure and functions
By newseditor
Posted 19 Oct
Posters
A chemical biology/modular…
By newseditor
Posted 22 Aug
Single-molecule covalent ma…
By newseditor
Posted 04 Jul
ASCO-2020-HEALTH SERVICES R…
By newseditor
Posted 23 Mar
ASCO-2020-HEAD AND NECK CANCER
By newseditor
Posted 23 Mar
ASCO-2020-GENITOURINARY CAN…
By newseditor
Posted 23 Mar