Cdkn1a-KO Mouse

Cdkn1a, also known as Cip1/Waf1/p21, is a well-established protein mainly recognized for its crucial role in the cell cycle. It induces cell cycle arrest by inhibiting cyclin-dependent kinases (CDKs), and is involved in pathways such as apoptosis, DNA damage response (DDR), and the regulation of stem cell fate. Cdkn1a can function as either an oncogene or a tumour suppressor, and its expression varies in different tumour types [1].

In cisplatin-induced acute kidney injury (AKI), Cdkn1a was identified as a key gene related to ferroptosis in p53 signaling. Knockdown of Cdkn1a in human renal tubular epithelial cells mitigated cisplatin-induced cell injury by reducing oxidative stress and ferroptosis, suggesting it could be a biomarker for early diagnosis and a therapeutic target in AKI [2]. A novel CDKN1A-JAZF1 gene fusion was reported in a case of low-grade endometrial stromal sarcoma arising from abdominal wall endometrioma, expanding the molecular landscape of this disease [3]. In esophageal cancer, CDKN1A polymorphisms were associated with EC risk in relation to age, with different genotypes showing associations with different age groups and subtypes of the cancer [4]. A lncRNA named SPUD, generated from CDKN1A by alternative polyadenylation, regulates p21 expression post-transcriptionally during DDR, highlighting lncRNA relevance in DDR progression and the cell-cycle [5]. The RNA binding protein RBM42 was found to regulate the splicing and translation of CDKN1A during DNA damage, fine-tuning p21 levels for genomic stability [6]. In an Iranian population, the AC genotype of CDKN1A rs1801270 polymorphism was associated with a reduced risk of colorectal cancer [7]. In gastric adenocarcinomas, the acetylation levels of histones associated with CDKN1A showed complex relationships with gene expression and lymph node metastasis [8].

In conclusion, Cdkn1a is a multifunctional gene involved in cell cycle regulation, apoptosis, DDR, and stem cell fate. Its study through various models, especially in relation to diseases like AKI, endometrial stromal sarcoma, esophageal cancer, colorectal cancer, and gastric adenocarcinomas, has provided insights into disease mechanisms and potential biomarkers or therapeutic targets. The complex regulatory mechanisms of Cdkn1a, such as through alternative polyadenylation and RNA-binding proteins, further emphasize its importance in biological processes and disease development.

References:

1. Manousakis, Evangelos, Miralles, Clàudia Martinez, Esquerda, Maria Guimerà, Wright, Roni H G. 2023. CDKN1A/p21 in Breast Cancer: Part of the Problem, or Part of the Solution? In International journal of molecular sciences, 24, . doi:10.3390/ijms242417488. https://pubmed.ncbi.nlm.nih.gov/38139316/

2. Gao, Qian, Chen, Jun-Ming, Li, Chen-Sui-Zi, Luo, Lian-Xiang, Li, Zhi-Ling. 2024. CDKN1A promotes Cis-induced AKI by inducing cytoplasmic ROS production and ferroptosis. In Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association, 193, 115003. doi:10.1016/j.fct.2024.115003. https://pubmed.ncbi.nlm.nih.gov/39353481/

3. Zhu, Tian-Hong, Zhang, Fu-Bin, Yan, Hui, Chen, Mei, Guan, Yu-Tao. . A novel CDKN1A-JAZF1 gene fusion in low-grade endometrial stromal sarcoma arising from endometriosis in abdominal wall cesarean section scar: A case report and literature review. In Taiwanese journal of obstetrics & gynecology, 61, 1082-1085. doi:10.1016/j.tjog.2022.04.010. https://pubmed.ncbi.nlm.nih.gov/36427980/

4. Kaya, Zehra, Karan, Burak Mugdat, Almalı, Necat. 2021. CDKN1A (p21 gene) polymorphisms correlates with age in esophageal cancer. In Molecular biology reports, 49, 249-258. doi:10.1007/s11033-021-06865-1. https://pubmed.ncbi.nlm.nih.gov/34743275/

5. Murphy, Michael R, Ramadei, Anthony, Doymaz, Ahmet, Zakusilo, George, Kleiman, Frida E. . Long non-coding RNA generated from CDKN1A gene by alternative polyadenylation regulates p21 expression during DNA damage response. In Nucleic acids research, 51, 11911-11926. doi:10.1093/nar/gkad899. https://pubmed.ncbi.nlm.nih.gov/37870464/

6. Ben-Oz, Bella M, Machour, Feras E, Nicola, Marian, Mandel-Gutfreund, Yael, Ayoub, Nabieh. 2023. A dual role of RBM42 in modulating splicing and translation of CDKN1A/p21 during DNA damage response. In Nature communications, 14, 7628. doi:10.1038/s41467-023-43495-6. https://pubmed.ncbi.nlm.nih.gov/37993446/

7. Zali, Neda, Savabkar, Sanaz, Tajali, Raziye, Hashemi, Mehrdad, Asadzadeh Aghdaei, Hamid. 2023. Association between CDKN1A gene rs1801270 polymorphisms and susceptibility to colorectal cancser in an Iranian population. In Nucleosides, nucleotides & nucleic acids, 42, 563-570. doi:10.1080/15257770.2023.2169934. https://pubmed.ncbi.nlm.nih.gov/36691945/

8. Wisnieski, Fernanda, Calcagno, Danielle Queiroz, Leal, Mariana Ferreira, Burbano, Rommel Rodríguez, Smith, Marília Cardoso. 2015. CDKN1A histone acetylation and gene expression relationship in gastric adenocarcinomas. In Clinical and experimental medicine, 17, 121-129. doi:10.1007/s10238-015-0400-3. https://pubmed.ncbi.nlm.nih.gov/26567008/