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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. [ABSTRACT FROM AUTHOR]

A virus with benefits: Oncolytic viruses, which kill cancer cells, have received increasing attention in recent years as the field has advanced toward biological and immune-based approaches to fighting cancer. To help further these viruses' cancer-fighting potential, Nakao et al. engineered an oncolytic vaccinia virus to deliver two cytokines that help stimulate antitumor immune responses. The authors successfully tested this approach in multiple immunocompetent mouse models, showing promising results in directly treated tumors and in distant tumors of the same type, as well as protection from rechallenge with tumor cells. The treatment was particularly effective in combination with immune checkpoint inhibitors, even in tumors unresponsive to checkpoint inhibitors alone. The immune status of the tumor microenvironment is a key indicator in determining the antitumor effectiveness of immunotherapies. Data support the role of activation and expansion of tumor-infiltrating lymphocytes (TILs) in increasing the benefit of immunotherapies in patients with solid tumors. We found that intratumoral injection of a tumor-selective oncolytic vaccinia virus encoding interleukin-7 (IL-7) and IL-12 into tumor-bearing immunocompetent mice activated the inflammatory immune status of previously poorly immunogenic tumors and resulted in complete tumor regression, even in distant tumor deposits. Mice achieving complete tumor regression resisted rechallenge with the same tumor cells, suggesting establishment of long-term tumor-specific immune memory. Combining this virotherapy with anti–programmed cell death-1 (PD-1) or anti–cytotoxic T lymphocyte antigen 4 (CTLA4) antibody further increased the antitumor activity as compared to virotherapy alone, in tumor models unresponsive to either of the checkpoint inhibitor monotherapies. These findings suggest that administration of an oncolytic vaccinia virus carrying genes encoding for IL-7 and IL-12 has antitumor activity in both directly injected and distant noninjected tumors through immune status changes rendering tumors sensitive to immune checkpoint blockade. The benefit of intratumoral IL-7 and IL-12 expression was also observed in humanized mice bearing human cancer cells. These data support further investigation in patients with non-inflamed solid tumors. [ABSTRACT FROM AUTHOR]

The authors demonstrate that Ge(100) surfaces containing metallic particles are etched anisotropically in water. This originates from the catalytic reduction of dissolved oxygen (O2) in water to water molecules (H2O) on the metallic particles, which is followed by the enhanced oxidation of Ge around the particles. The soluble nature of Ge oxide (GeO2) in water promotes the formation of inverted pyramidal etch pits composed of (111) microfacets. On the basis of the results, the authors propose strategies for avoiding unwanted surface roughening during the wet cleaning of Ge. [ABSTRACT FROM AUTHOR]

The PHLDA family (pleckstrin homology‐like domain family) of genes consists of 3 members: PHLDA1, 2, and 3. Both PHLDA3 and PHLDA2 are phosphatidylinositol (PIP) binding proteins and function as repressors of Akt. They have tumor suppressive functions, mainly through Akt inhibition. Several reports suggest that PHLDA1 also has a tumor suppressive function; however, the precise molecular functions of PHLDA1 remain to be elucidated. Through a comprehensive screen for p53 target genes, we identified PHLDA1 as a novel p53 target, and we show that PHLDA1 has the ability to repress Akt in a manner similar to that of PHLDA3 and PHLDA2. PHLDA1 has a so‐called split PH domain in which the PH domain is divided into an N‐terminal (β sheets 1‐3) and a C‐terminal (β sheets 4‐7 and an α‐helix) portions. We show that the PH domain of PHLDA1 is responsible for its localization to the plasma membrane and binding to phosphatidylinositol. We also show that the function of the PH domain is essential for Akt repression. In addition, PHLDA1 expression analysis suggests that PHLDA1 has a tumor suppressive function in breast and ovarian cancers. Through a comprehensive screening for p53 target genes, we identified pleckstrin homology‐like domain family, member 1 (PHLDA1) as a novel p53 target, and we show that PHLDA1 has the ability to repress Akt in a manner similar to that of other PHLDA family proteins. We show that the PH domain of PHLDA1 is responsible for its localization to the plasma membrane, and PHLDA1 has the ability to bind to phosphatidylinositols and repress Akt. In addition, PHLDA1 expression analysis suggests that PHLDA1 has a tumor suppressive function in breast and ovarian cancers. [ABSTRACT FROM AUTHOR]

The tumor suppressor p53 functions by inducing the transcription of a collection of target genes. We previously attempted to identify p53 target genes by microarray expression and Ch IP-sequencing analyses. In this study, we describe a novel p53 target gene, FUCA1, which encodes a fucosidase. Although fucosidase, α- l-1 ( FUCA1) has been reported to be a lysosomal protein, we detected it outside of lysosomes and observed that its activity is highest at physiological pH. As there is a reported association between fucosylation and tumorigenesis, we investigated the potential role of FUCA1 in cancer. We found that overexpression of FUCA1, but not a mutant defective in enzyme activity, suppressed the growth of cancer cells and induced cell death. Furthermore, we showed that FUCA1 reduced fucosylation and activation of epidermal growth factor receptor, and concomitantly suppressed epidermal growth factor signaling pathways. FUCA1 loss-of-function mutations are found in several cancers, its expression is reduced in cancers of the large intestine, and low FUCA1 expression is associated with poorer prognosis in several cancers. These results show that protein defucosylation mediated by FUCA1 is involved in tumor suppression. [ABSTRACT FROM AUTHOR]

Control of the microroughness of Ge surfaces is required to realize field-effect transistors with high performances. We propose a novel surface-flattening process for Ge that involves the preferential transformation of surface protrusions on Ge into soluble GeO2 with the help of a catalyst in water. To carry out this process, we developed a setup comprising a catalyst plate covered with a Pt film in contact with a Ge surface in saturated O2-dissolved water. The role of the metallic film is to enhance the oxygen reduction reaction in water that accompanies the oxidation of protrusions or microbumps on a Ge surface. After presenting the fundamental etching properties of a Ge surface treated with this metal-assisted chemical etching method, we demonstrate that our water-based process creates a flattened Ge surface that has few protrusions with a lateral size on the order of 10 nm. [ABSTRACT FROM AUTHOR]