p53 is a tumor suppressor gene and is regarded as one of the most crucial genes in protecting humans against cancer. The protein Mdm2 and its homolog MdmX serve as negative regulators of p53. In nearly half of cancer cells, there is an overexpression of Mdm2 and MdmX, which inhibit p53 activity. Furthermore, Mdm2’s E3 ubiquitin ligase activity promotes the ubiquitination and degradation of p53. Therefore, blocking the interaction between p53 and Mdm2/MdmX to prevent the degradation of wild-type p53 is an effective strategy for inhibiting tumor growth. This paper primarily discusses the regulatory relationship between p53, MdmX and Mdm2, and provides a review of the current status of p53-Mdm2/MdmX inhibitors. It aims to offer a theoretical foundation and research direction for the future discovery and design of targeted inhibitors against the p53-Mdm2/MdmX interaction.

The p53 gene is one of the genes most closely associated with human tumors and has become a popular target for tumor drug design. Currently, p53-based gene therapy techniques have been developed, but these therapies face challenges such as immaturity, high safety hazards, limited efficacy, and low patient acceptance. However, researchers are no less enthusiastic about the treatment because of its theoretical potential to treat cancer. In this paper, the advances in p53-based gene therapy and related nucleic acid delivery technologies were reviewed and prospected in order to support further development in this field.

4-Androstene-3,17-dione (4-AD) and 22-hydroxy-23,24-bisnorchol-4-ene-3-one (BA) are the most important and representative C19- and C22-steroidal materials. The optimalization of sterol production with mycobacterial phytosterol conversion has been investigated for decades. One of the major challenges is that current industrial mycobacterial strains accumulate unignorable impurities analogous to desired sterol intermediates, significantly hampering product extractions and refinements. Previously, we identified Mycobacterium neoaurum HGMS2 as an efficient 4-AD-producing strain (Wang et al. in Microb Cell Fact. 19:187, 2020). Recently, we have genetically modified the HGMS2 strain to remove its major impurities including ADD and 9OH-AD (Li et al. in Microb Cell Fact. 20:158, 2021). Unexpectedly, the modified mutants started to significantly accumulate BA compared with the HGMS2 strain. In this work, while we attempted to block BA occurrence during 4-AD accumulation in HGMS2 mutants, we identified a few loop pathways that regulated metabolic flux switching between 4-AD and BA accumulations and found that both the 4-AD and BA pathways shared a 9,10-secosteroidial route. One of the key enzymes in the loop pathways was Hsd4A1, which played an important role in determining 4-AD accumulation. The inactivation of the hsd4A1 gene significantly blocked the 4-AD metabolic pathway so that the phytosterol degradation pathway flowed to the BA metabolic pathway, suggesting that the BA metabolic pathway is a complementary pathway to the 4-AD pathway. Thus, knocking out the hsd4A1 gene essentially made the HGMS2 mutant (HGMS2^Δhsd4A1) start to efficiently accumulate BA. After further knocking out the endogenous kstd and ksh genes, an HGMS2^Δhsd4A1 mutant, HGMS2^{Δhsd4A1/Δkstd1}, enhanced the phytosterol conversion rate to BA in 1.2-fold compared with the HGMS2^Δhsd4A1 mutant in pilot-scale fermentation. The final BA yield increased to 38.3 g/L starting with 80 g/L of phytosterols. Furthermore, we knocked in exogenous active kstd or ksh genes to HGMS2^{Δhsd4A1/Δ kstd1} to construct DBA- and 9OH-BA-producing strains. The resultant DBA- and 9OH-BA-producing strains, HGMS2^{Δhsd4A1/kstd2} and HGMS2^{Δkstd1/Δhsd4A1/kshA1B1}, efficiently converted phytosterols to DBA- and 9OH-BA with the rates of 42.5% and 40.3%, respectively, and their final yields reached 34.2 and 37.3 g/L, respectively, starting with 80 g/L phytosterols. Overall, our study not only provides efficient strains for the industrial production of BA, DBA and 9OH-BA but also provides insights into the metabolic engineering of the HGMS2 strain to produce other important steroidal compounds.

Cellular protein–protein interactions are largely dependent on the activities of signaling proteins. Here, we present a technique to tune gene expression at translation level based on G418-inducibl... METHOD SUMMARY A PTC-on system to tune gene expression by G418 in a dose-dependent mode at translation level based on readthrough premature termination codon was constructed. The system was validat...