Research Article - (2023) Volume 7, Issue 2
Received: 04-Nov-2022, Manuscript No. IPJVMS-22-14662; Editor assigned: 07-Nov-2022, Pre QC No. IPJVMS-22-14662 (PQ); Reviewed: 21-Nov-2022, QC No. IPJVMS-22-14662; Revised: 27-Jan-2023, Manuscript No. IPJVMS-22-14662 (R); Published: 03-Feb-2023, DOI: 10.36648/2574-2868.7.2.008
Absence of WDR13 is known to be involved in pancreatic, colon and uterine hyper proliferation. However, a recent study showed its anti-proliferative role liver regeneration in response to hepatotoxins. These findings intrigued to study the role of WDR13-null condition in Trp53 knockout mouse to study the tumor predisposition and survival. We report absence of Wdr13 in Trp53 null background alleviates the tumor load, in turn increasing total survival in mouse model.
Hepatotoxins; Pancreatic; Tumor; Uterine; Proliferation
Cancer is a grave disease that arises because of abnormal cell growth and can invade or spread to other body parts. The rate of occurrence of cancer worldwide is increasing at an alarming rate, 12.7 million cases in 2008. The p53 is a key protein for tumor suppression and found to be mutated in over half of all human cancers. Individuals with Li–Fraumeni syndrome, a classic cancer predisposition disorder, inherit mutant p53 allele and are highly cancer prone. The null mutation of p53 does not display embryonic lethality but have decreased survival as compared to wild type mice; the majority of p53 mice succumbed to tumors between 2-9 months of age.
Earlier studies on WDR13 suggest its involvement in cell cycle regulation in different tissues like pancreas, liver adipose, colon and uterus. WDR13 expression has also been reported in many human cancers like breast cancer, glioma, Ewing’s sarcoma, lung cancer, melanoma, testes cancer, ovary teratocarcinoma, and urothelial cancer. High expression of WDR13 in above mentioned cancers further strengthens the postulate that WDR13 has a vital role in regulating cell cycle.
Therefore, it was interesting to study the cancerous phenotype after the introgression of Wdr13-null mutation in a cancer mouse model. To test above proposition, Wdr13-10 mice were mated with p53−/− mice and Wdr13−/10/p53−/− double knockout mouse was generated [1-6].
Animals
The animals were approved by the Institutional Animal Ethics Committee (IAEC) of CSIRCCMB, Hyderabad, India (trial registration number 20/1999/CPCSEA dated 10/3/99). C57Bl/6J Wdr13−/0 male mice were mated with p53−/− females to obtain double heterozygous animals. Then the littermates were crossed to obtain Double Knock Out (DKO) animals. Mice were housed at 22°C-25°C temperature with 12 hr light/dark cycle. All the mice were fed standard chow for entire experimental duration ad libitum. 20 animals per group were used, DKO were 21. Severely ailing mice were sacri ced according to the IAEC rules.
Genotyping-Wdr13 genotyping was done as explained and p53 genotyping was performed as described by Jacks, et al. [7-11].
The absence of WDR13 in p53−/− mice enhanced their longevity: While all the p53−/− mice died by 36 weeks of age the double knockout mice survived more than a year, as determined by Kaplan-Meier estimate (Figure 1).
Figure 1: Kaplan Miere survival graph of all genotypes. Survival of Double Knockout (DKO) mice is significantly (p<0.0001, Log rank Mantel-Cox Test) higher than the p53−/− mice.
The double knockout mice were comparatively healthy and had lower tumor load at 6 months of age as compared to p53−/− mice. Further analyses of the tissues revealed significant difference in the Wdr13−/0/p53−/− double knockout mice and the p53−/− mice at 6 months.
The results establish that the absence of WDR13 in p53−/− mice is beneficial for survival of p53−/− mice as the double knockout mice had better longevity. The double knockout mice also had lesser tumor load as compared to p53−/− mice. Role of WDR13 in cell cycle regulation in different tissues has been attributed to PPARγ. Wdr13−/0 mice is known to have higher expression levels of PPARγ in adipose and in liver. Activation of PPARγ slows the regeneration of liver in CCl4 administered Wdr13−/0 mice. The promoter of Pparγ has an AP1 site and WDR13 is known to bind AP1 sites with c-Jun.
PPARγ is known to stimulate apoptosis in cancer cells thereby ameliorating cancer phenotype. PPARγ agonists have been used to study apoptosis in cell lines. In thyroid cancer cells lines, troglitazone demonstrated increased c-Myc expression without changing the expression of Bcl-2 or Bax [12-14].
In the light of these observations, deregulation of PPARγ in absence of WDR can be attributed to be involved in amelioration of cancerous phenotype of p53−/− mice. Studying the expression levels of PPARγ and its target proteins in different tissues of Wdr13−/0/p53−/− mice is an interesting venue for future research.
The animals were approved by the Institutional Animal Ethics Committee (IAEC) of CSIRCCMB, Hyderabad, India (trial registration number 20/1999/CPCSEA dated 10/3/99).
APM conceived the idea and performed all the experiments. APM wrote the manuscript. BJL helped in maintenance and breeding of mice.
The work was done in Dr. Satish Kumar l ab facility i n CCMB, Hyderabad, India.
[Crossref] [Google Scholar] [PubMed]
[Crossref] [Google Scholar] [PubMed]
[Crossref] [Google Scholar] [PubMed]
[Crossref] [Google Scholar] [PubMed]
[Crossref] [Google Scholar] [PubMed]
[Crossref] [Google Scholar] [PubMed]
[Crossref] [Google Scholar] [PubMed]
[Crossref] [Google Scholar] [PubMed]
[Crossref] [Google Scholar] [PubMed]
[Crossref] [Google Scholar] [PubMed]
[Crossref] [Google Scholar] [PubMed]
[Crossref] [Google Scholar] [PubMed]
Citation: Mishra AP, Lakshmi JB (2023) Absence of WDR13 in p53-Null Mice Increases Longevity. J Veterinary Med. 7:008
Copyright: © 2023 Mishra AP, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
