The common polymorphism of p53 at codon 72, either encoding proline or arginine, has drawn attention as a genetic factor associated with clinical outcome or cancer risk for the last 2 decades. We now show that these two polymorphic variants differ in protein structure, especially within the N-terminal region and, as a consequence, differ in post-translational modification at the N terminus. The arginine form (p53-72R) shows significantly enhanced phosphorylation at Ser-6 and Ser-20 compared with the proline form (p53-72P). We also show diminished Mdm2-mediated degradation of p53-72R compared with p53-72P, which is at least partly brought about by higher levels of phosphorylation at Ser-20 in p53-72R. Furthermore, enhanced p21 expression in p53-72R-expressing cells, which is dependent on phosphorylation at Ser-6, was demonstrated. Differential p21 expression between the variants was also observed upon activation of TGF-␤ signaling. Collectively, we demonstrate a novel molecular difference and simultaneously suggest a difference in the tumor-suppressing function of the variants.

OBJECTIVE: The suppression of body odour following the use of shampoos or soaps containing the anti-fungal agent miconazole nitrate (MCZ) has been recognized anecdotally. To determine whether MCZ could play a role in the suppression of body odour through inhibiting squalene oxidation. METHODS: A prospective study recruited 54 elderly subjects residing in a nursing facility who needed bathing assistance. Subjects bathed with three types of body soap over a 6-week study period (regular soap, sample soap (soap containing MCZ), control soap; 2 weeks per type of soap). Body odour was evaluated based on olfactory assessment of the subjects and their clothing. The subjects and the examiners were blinded to the type of soap (sample or control) being used during the study. An analysis using GC/MS was also carried out to identify the volatile compounds associated with body odour. RESULTS: Suppression of unpleasant body odour of the neck and axilla was reported in subjects who used the sample soap. Three common volatile compounds were detected from the T-shirts worn by the subjects: 2-ethylbutanal, 6-methyl-5-hepten-2-one, and geranylacetone. The occurrence of these compounds was reduced using the sample soap. CONCLUSION: Our findings suggest that MCZ could play a role in the suppression of body odour.R esum e OBJECTIF: La suppression de l'odeur corporelle suite a l'utilisation de shampooings ou des savons contenant l'agent anti-fongique nitrate de miconazole (MCZ) a et e observ ee de fac ßon anecdotique. Le but due l' etude etait de d eterminer si MCZ pouvait jouer un rôle dans la suppression de l'odeur corporelle en inhibant l'oxydation du squal ene.

The tumor suppressor gene p53 encodes a transcriptional activator that has two transactivation domains (TAD) located in its amino terminus. These two TAD can transactivate genes independently, and at least one TAD is required for p53 transactivation function. The 1st TAD (a.a. 1-40) is essential for the induction of numerous classical p53 target genes, while the second TAD (a.a. 41-61) suffices for tumor suppression, although its precise molecular function remains unclear. In this study, we comprehensively identified the sites to which p53 lacking the 1st TAD (Δ1stTAD-p53) binds, as well as its potential target genes. We found that the binding sequences for Δ1stTAD-p53 are divergent and include not only the canonical p53 consensus binding sequences but also sequences similar to those recognized by a number of other known transcription factors. We identified and analyzed the functions of three Δ1stTAD-p53 target genes, PTP4A1, PLK2 and RPS27L. All three genes were induced by both full-length p53 and Δ1stTAD-p53, and were dependent on the transactivation activity of the 2nd TAD.We also found that two of these, PTP4A1 and PLK2, are endoplasmic reticulum (ER) stress-inducible genes. We found that upon ER stress, PTP4A1 suppresses apoptosis while PLK2 induces apoptosis. These results reveal a novel Δ1stTAD-p53 downstream pathway that is dependent on the transcription activation activity of the 2nd TAD. K E Y W O R D S endoplasmic reticulum stress, p53, p53 isoform, Suzuki, transactivation domain, tumor suppressor S U PP O RTI N G I N FO R M ATI O N Additional supporting information may be found online in the Supporting Information section. How to cite this article: Suzuki S, Tsutsumi S, Chen Y, et al. Identification and characterization of the binding sequences and target genes of p53 lacking the 1st transactivation domain. Cancer Sci. 2020;111:451-466. https ://doi.

Botulinum neurotoxins produced by Clostridium botulinum cause flaccid paralysis by inhibiting neurotransmitter release at peripheral nerve terminals. Previously, we found that neurons derived from the murine P19 embryonal carcinoma cell line exhibited high sensitivity to botulinum neurotoxin type C. In order to prove the utility of P19 cells for the study of the intracellular mechanism of botulinum neurotoxins, ganglioside-knockout neurons were generated by deletion of the gene encoding beta-1,4 N-acetylgalactosaminyltransferase 1 in P19 cells using the clustered regularly interspaced short palindromic repeats combined with Cas9 (CRISPR/Cas9) system. By using this system, knockout cells could be generated more easily than with previous methods. The sensitivity of the generated beta-1,4 N-acetylgalactosaminyltransferase 1-depleted P19 neurons to botulinum neurotoxin type C was decreased considerably, and the exogenous addition of the gangliosides GD1a, GD1b, and GT1b restored the susceptibility of P19 cells to botulinum neurotoxin type C. In particular, addition of a mixture of these three ganglioside more effectively recovered the sensitivity of knockout cells compared to independent addition of GD1a, GD1b, or GT1b. Consequently, the genome-edited P19 cells generated by the CRISPR/Cas9 system were useful for identifying and defining the intracellular molecules involved in the toxic action of botulinum neurotoxins.