Mini Review - (2024) Volume 16, Issue 6
A Mini Review on an Enigma of Mutant P53
Musadiq Ali**
*Correspondence:
Musadiq Ali*, Department of Microbiology and Molecular Genetics, Department of Microbiology and Molecular Genetics,
Pakistan,
Email:
Department of Microbiology and Molecular Genetics, Department of Microbiology and Molecular Genetics, Pakistan
Received: 06-Aug-2021, Manuscript No. jcst-22-001-Pre-Qc-22;
Editor assigned: 13-Aug-2021, Pre QC No. jcst-22-001-Pre-Qc-22;
Reviewed: 27-Aug-2021, QC No. jcst-22-001-Pre-Qc-22;
Revised: 30-May-2022, Manuscript No. jcst-22-001-Pre-Qc-22;
Published:
29-Jul-2022
, DOI: 10.37421/1948-5956.2024.16.679
Abstract
There are many genes that have been explored in relation with cancer. But 50 percent of cancers occur due to mutation in P53. In the beginning, there was a thought that P53 act as an oncogenic protein instead of suppressing cancers. Now we have reached on conclusion that mutant P53 instead of wild type, act as an oncogenic protein. Through research carried out in the past, it has been concluded that gain of function mutation in the P53 has early onset of cancer as compared to mutant P53 with loss of function. A number of hotspots for mutation in P53 such as R175, G245, R248, R249, R273 and R282 have been identified in the past. Mutant P53 interact and inhibit proteins normal functioning such as p63, MRE11, Rad51-NSB complex, p73 and Sp-1. Mutant P53 also lead to enhance functioning of protein such as SREBP, NF-Y, VDR, ETS2 and NRF2. For proper folding of wild type P53 Zn+2 is necessary. There are microRNAs which are under the control of mutant P53. Mostly, PRIMA-1 analog has been used to reactivate the mutant P53 to wild type.
Introduction
P53 is one of the most studied tumor suppressor proteins.
Mutations in P53 have been detected in many different types of
tumors. For the first 10 years of discovery, P53 was
considered to be an oncogene. This mistake in the initial
classification of P53 was due to the fact that P53 gene that had been
cloned and used in the initial experiments encoded a mutant
version of the wild-type P53 gene. After 30 years of P53
discovery, we have come to conclusion that mutant versions
of P53 act as oncogenic proteins. P53 is the most commonly
mutated gene in human cancers [1]. Missense mutations in the
DNA binding domain of P53 lead to tumors of different types. In
some cases nonsense or frame shift mutations occurs which
leads to suppression of P53 expression [2].
The powerful transcription factor p53 activates hundreds of genes,
many of which are tissue- and cell-specific, by binding to two
repeats of a particular DNA sequence (50-
RRRCWWGYYY-30) as a tetramer. This sequence often
appears within 10 kb of the promoter, while it can also appear at
enhancers farther away. Numerous cellular cues, which
frequently detect DNA damage, stress, and incorrect oncogene
activation, cause p53 to be stabilised and activated. These p53-
regulated genes serve a variety of purposes, including cell
death (Puma, Noxa, Bax), cell cycle arrest (p21, Btg2, Ptprv), cell
senescence (p21, Pml, Pai-1), and modifying metabolic status for
Discussion
Mostly, PRIMA-1 analogs has been used to restore the activity of
mutant P53 to wild type P53. PRIMA-1 is rapidly converted to other
compounds, including MQ, which can bind to both mutant P53 and
wild-type P53. Although mechanism that reactivate the mutant P53 to
wild type remains still mystery. In some cases, unfolded P53 behave
like mutant P53 which leads to invasion and metastasis. Functioning
of unfolded wild-type P53, grown under hypoxia in tumor cell lines,
can be restored by PRIMA-1 treatment. Cholesterol lowering drug
statin has been found to induce degradation of misfolded P53
mutants with minimal effects on wild-type P53 and DNA contact
mutants. Statin impairs the interaction between mutant P53 and
DNAJA1, a Hsp40 family member. Knockdown of DNAJA1 leads to
mutant P53 degradation; on the other hand over expression of
DNAJA1 inhibit the degradation of mutant P53.
Conclusion
Mutant p53 plays a major role in causing different type of tumors. In this review, we have briefly discussed some aspect of mutant p53 that have been described in the literature in the recent past. It is the need of hour to look at mutant p53 in detail especially its interaction with the DNA that will provide insight about cause of cancers. Secondly, we can look for anticancer drug which can directly inhibit Mutant p53 activity.
