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P53

Official Full Name
transformation related protein 53
Synonyms
bbl; bfy; bhy; p44; p53; Tp53

Cat.No. Product Name Price
CDCL185593Mouse P53 ORF clone(NM_011640.3)Inquiry

Recent research Progress

TP53 is the most common mutated gene in human cancers. Wild-type p53 is a sequence-specific transcription factor that, when activated by various stresses such as DNA damage, oncogenic signaling, or nutrient depletion, promotes cellular outcomes such as cell arrest, cell death, aging, and metabolic changes depending on the extent and context of the stress. In human cancer, p53 maintains missense mutations primarily in its conserved DNA binding domain. A few residues (about 5 to 6) that mutate at very high frequencies in this region are called hotspot mutations. It has been reported that p53 hotspot mutations and chromatin associations alter the transcriptional profile of cells, leading to changes in cancer cells.

P53Figure 1. Mutant p53 and mutant p53 complexes interacts with transcriptionfactors.

P53 and HGSOC

High-grade serous ovarian cancer (HGSOC) is the most deadly gynecological cancer,that usually leads to chemically resistant diseases. The p53 protein is a key transcription factor that regulates cellular homeostasis. Due to genetic mutations, most of the HGSOC p53 is not active. However, genetic mutations are not the only cause of inactivation of p53. Aggregation of p53 protein has been found in different types of cancer and may result in impaired normal transcriptional activation and pro-apoptotic function of p53. In a unique population of HGSOC cancer cells with cancer stem cell characteristics, p53 protein aggregation is associated with p53 inactivation and platinum resistance. When these cancer stem cells differentiate into chemosensitive progeny, they lose tumor initiating ability and p53 aggregates. In addition to the association of p53 aggregation with chemoresistance in HGSOC cells, overexpression of the p53 positive regulator p14ARF inhibits MDM2-mediated p53 degradation and leads to p53 turnover imbalance, thereby promoting the formation of p53 aggregates. Using in vitro and in vivo models, inhibition of p14ARF has been shown to inhibit p53 aggregation and sensitize cancer cells to platinum therapy. Furthermore, by two-dimensional gel electrophoresis and mass spectrometry, it has been found that aggregated p53 may play a unique role by interacting with proteins essential for cancer cell survival and tumor progression.

P53 and medulloblastoma

Rebecca M et al. studied the transgenic model of MYCN-driven medulloblastoma and found the spontaneous development of Trp53 inactivating mutations. In this model, loss of p53 function produces an aggressive tumor that mimics the characteristics of recurrent human tumors that incorporate P53-MYC dysfunction. Recovery of p53 activity and genetic and therapeutic inhibition of MYCN reduced tumor growth and prolonged survival. These findings identify P53-MYC interactions in the recurrence of medulloblastoma as biomarkers of clinically invasive diseases that can be targeted for treatment.

P53 and breast cancer

The p53 mutant affects the expression of numerous genes at the transcriptional level to mediate tumorigenesis. Vascular endothelial growth factor receptor 2 (VEGFR2), a major functional VEGF receptor that mediates endothelial cell vascularization, has been identified as a mutated p53 transcriptional target in a variety of breast cancer cell lines. Up-regulation of VEGFR2 mediates the effect of mutant p53 on cell growth under two-dimensional (2D) and three-dimensional (3D) culture conditions. The mutant p53 binds near the transcription initiation site of the VEGFR2 promoter and maintains an open conformation at this position. Relatedly, the mutant p53 interacts with the SWI/SNF complex, which is required for the reconstitution of the VEGFR2 promoter. By querying a single gene regulated by the mutant p53 and performing RNA sequencing, the results indicated that >40% of all mutant p53-regulated gene expression was mediated by SWI/SNF. Mutant p53 affects the transcription of VEGFR2 and numerous other genes by promoter remodeling through interaction with and possible regulation of the SWI/SNF chromatin remodeling complex. Therefore, not only mutant p53 tumors are susceptible to anti-VEGF therapy, but also affecting SWI/SNF tumor suppressor function in mutant p53 tumors may also have therapeutic potential.

In summary, there is increasing evidence that mutations in the p53 gene of the tumor suppressor gene are the most common in the genetic variation of human cancer, occurring in more than 50% of human cancers. Most p53 mutations are missense mutations that cause dysfunctional p53 protein to accumulate in tumors. These mutants often have carcinogenic functions to gain activity and exacerbate the malignant properties of cancer cells, such as metastasis and drug resistance. Therefore, further study of the mechanism of action of P53 in cancer will provide new insights into the diagnosis and treatment of cancer.

References:

  1. Ashley B, et al. p53 in the DNA-Damage-Repair Process. Cold Spring Harb Perspect Med, 2016, 6:a026070
  2. Tang Juanjuan, et al. p53-mediated autophagic regulation: A prospective strategy for cancer therapy. Cancer Letters, 2015, 363:101-107
  3. Yang-Hartwich, et al. p53 protein aggregation promotes platinum resistance in ovarian cancer. Oncogene, 2015, 34:3605-3616
  4. Rebecca M, et al. Combined MYC and P53 Defects Emerge at Medulloblastoma Relapse and Define Rapidly Progressive, Therapeutically Targetable Disease. Cancer Cell, 2015, 27(12):72-84
  5. Neil T, et al. Mutant p53 cooperates with the SWI/SNF chromatin remodeling complex to regulate VEGFR2 in breast cancer cells. Genes & Development, 2016, 29:1298-1315

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