Loss of tyrosine 211 phosphorylation of proliferating cell nuclear antigen (PCNA) enhances postnatal mammary gland development

Yi-Chun Shen, Center for Molecular Medicine, China Medical University Hospital, Taichung 404327, Taiwan
You-Zhe Lin, Cancer Biology and Precision Therapeutics Center, China Medical University, Taichung 406040, Taiwan
Wan-Rong Wu, Graduate Institute of Biomedical Sciences, College of Medicine, China Medical University, Taichung 406040, Taiwan
Pei-Le Lin, Graduate Institute of Biomedical Sciences, College of Medicine, China Medical University, Taichung 406040, Taiwan
Chien-Ching Liao, Graduate Institute of Biomedical Sciences, College of Medicine, China Medical University, Taichung 406040, Taiwan
Feng-Chi Chung, Cancer Biology and Drug Discovery Ph.D. Program, China Medical University, Taichung 406040, Taiwan
Chia-Yun Chen, School of Medicine, China Medical University, Taichung 406040, Taiwan
Ching-Yu Weng, School of Medicine, China Medical University, Taichung 406040, Taiwan
Shao-Chun Wang, Center for Molecular Medicine, China Medical University Hospital, Taichung 404327, TaiwanFollow

Abstract

The intricately orchestrated progression of mammary tissue development involves the precise coordination of gland differentiation and cellular proliferation. Nevertheless, the understanding of the role and regulatory mechanisms governing the DNA replication machinery in mammary gland development remains limited. Given the essential role of DNA replication in the viability of living cells, any genetic disturbance to its replicative function, in any form, will impede organ development. This circumstance poses a technical challenge in elucidating the potential function of cell proliferation in mammary morphogenesis. PCNA is crucial in DNA replication, playing a pivotal role in the development of complete eukaryotic organisms. The phosphorylation of PCNA at tyrosine 211 (Y211) has been demonstrated to play a significant role in supporting replication forks and, consequently, cell proliferation. Therefore, the utilization of a knock-in mouse model, wherein the Y211 residue of PCNA is replaced with phenylalanine (211F), presents an opportunity to evaluate the impact of reduced cell proliferation potential on mammary gland development. Interestingly, the lack of Y211 phosphorylation did not significantly impact the rates of proliferation or cell death in the mammary gland. In contrast, the absence of Y211PCNA led to an increased, rather than reduced, growth of the mammary gland. This was evident in assessments of gland length and the number of terminal end buds (TEBs) in both postnatal and virgin mammary glands. Notably, this observation correlated with an elevation in tissue stemness within the 211F glands compared to the WT glands. Additionally, it was consistent with the greater body weight gains observed in 211F pups compared to WT pups during the weaning period. Our findings unveil an unexpected aspect that may carry significance for mammary development. This newfound is associated with the regulation of a central component within the DNA replication machinery, providing insights into the intricate interplay governing mammary tissue expansion.

Keyword: mammary gland; PCNA; phosphorylation

Recommended Citation

Shen, Yi-Chun; Lin, You-Zhe; Wu, Wan-Rong; Lin, Pei-Le; Liao, Chien-Ching; Chung, Feng-Chi; Chen, Chia-Yun; Weng, Ching-Yu; and Wang, Shao-Chun (2024) "Loss of tyrosine 211 phosphorylation of proliferating cell nuclear antigen (PCNA) enhances postnatal mammary gland development," BioMedicine: Vol. 14 : Iss. 3 , Article 5.
DOI: 10.37796/2211-8039.1462