Abstract
p53 is possibly the most important mammalian tumor suppressor and it is mutated or lost in more than half of all human cancers. The stability of p53 is primarily determined by the RING domain E3 ubiquitin ligase Hdm2, which targets p53 for proteasomal degradation, restraining the potent activity of p53 and enabling cell survival and proliferation. UBE4B has been shown to physically interact with p53 and Hdm2 and to negatively regulate p53 stability and function. However, no one has determined whether UBE4B promotes p53 degradation in breast cancer. In this study, UBE4B promoted the degradation and ubiquitination of p53 to inhibit the apoptosis of cancer cells and promote tumorigenesis. Our results indicate that UBE4B regulates p53 in breast cancer and could be a viable target for developing new therapeutic strategies for breast cancer treatment.
Highlights
Ubiquitin (Ub) is a highly conserved 8 kDa protein that covalently attaches to the lysine (Lys) residues of target proteins
The p53 protein was heavily ubiquitinated in the presence of Hdm2 or UBE4B and was more heavily ubiquitinated by the coexpression of Hdm2 and UBE4B
The p53 protein and its gene, TP53, were identified in 1979 [9,10,11]. p53 plays a critical role in cancer prevention because it suppresses tumorigenesis by inducing cell cycle arrest and apoptosis through its transcriptional activity. p53 is a tumor suppressor genes most frequently inactivated in cancer [12]
Summary
Ubiquitin (Ub) is a highly conserved 8 kDa protein that covalently attaches to the lysine (Lys) residues of target proteins. Proteins are reliant on the quantity of attached Ub moieties and can be modified through mono-ubiquitination or polyubiquitination. The UBE4B gene, which is located in the 1p36 region and encodes an E3/E4 ubiquitin ligase, was previously known as UFD2 in yeast [6]. This gene catalyzes Ub chain assembly in conjunction with E1, E2, and E3 and binds to the Ub moieties of preformed conjugates [5]
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