Biology subjects

Yamakawa, H.

Publications and source records attributed to Yamakawa, H..

4 recordsLinked to original sources

bioRxiv2026

CDK12/13 inhibitor, CTX-439, suppresses tumor growth and potentiates BCL-2 family blockade

CDK12 and CDK13 (CDK12/13) regulate transcription by phosphorylating Serine 2 (S2) of the C-terminal domain of RNA polymerase II and have been proposed as therapeutic targets in cancer. Here we report the development of CTX-439, a novel, orally bioavailable, ATP-competitive small-molecule CDK12/13 inhibitor. CTX-439 specifically inhibits S2 phosphorylation and downregulates many genes including those involved in DNA damage repair, thereby exerting a profound anti-cancer effect in vitro and in vivo including breast cancer PDX models. A CRISPR activation screen identified BCL-2 and BCL-xL, anti-apoptotic BCL-2 family members, as genes that when upregulated confer resistance to CTX-439. Simultaneous inhibition of BCL-2/BCL-xL and CDK12/13 rapidly induced apoptosis and significantly suppressed xenograft tumor growth. Mechanistically, CTX-439 downregulates MCL1 protein levels through transcriptional readthrough, shifting cell survival dependency to BCL-2 and BCL-xL. Our study provides novel insights into the anti-tumor effect of CDK12/13 inhibition and proposes a new combination therapy strategy with anti-apoptotic BCL-2 family inhibitors, which may improve therapeutic outcomes in cancer treatment.

cancer biology↗

bioRxiv2023

The androgen receptor in mesenchymal progenitors regulates skeletal muscle mass via Igf1 expression in male mice.

Androgens exert their effects primarily by binding to the androgen receptor (AR), a ligand-dependent nuclear receptor. While androgens have anabolic effects on skeletal muscle, previous studies reported that AR functions in myofibers to regulate skeletal muscle quality, rather than skeletal muscle mass. Therefore, the anabolic effects of androgens are exerted via extra-myofiber cells or tissues. In this context, the cellular and molecular mechanisms of AR in mesenchymal progenitors, which play a crucial role in maintaining skeletal muscle homeostasis, remain largely unknown. In this study, we demonstrated expression of AR in mesenchymal progenitors and found that targeted AR ablation in mesenchymal progenitors reduced limb muscle mass in mature adult, but not young or aged, male mice, although fatty infiltration of muscle was not affected. The absence of AR in mesenchymal progenitors led to remarkable perineal muscle hypotrophy, regardless of age, due to abnormal regulation of transcripts associated with cell death and extracellular matrix organization. Additionally, we revealed that AR in mesenchymal progenitors regulates the expression of insulin-like growth factor 1 (Igf1), and that IGF1 administration prevents perineal muscles atrophy in a paracrine manner. These findings indicate that the anabolic effects of androgens regulate skeletal muscle mass via, at least in part, AR signaling in mesenchymal progenitors. Significance statementAndrogens are essential not only for the development of male sexual characteristics but also for a range of physiological functions, including the regulation of skeletal muscle growth and function. Understanding the functionality of the androgen receptor (AR) is essential for comprehending the mechanisms through which androgens exert their effects on skeletal muscles, as these effects are mediated through AR binding. We demonstrate that AR is expressed in mesenchymal progenitors, which play a vital role in muscle homeostasis, and regulates the expression of insulin-like growth factor 1 (Igf1)--a key player in skeletal muscle growth--to control muscle mass. Our study provides significant insights into potential therapeutic strategies for addressing muscle atrophy conditions like sarcopenia.

molecular biology↗

bioRxiv2018

Dynamic embedding of salience coding in hippocampal spatial maps

Hippocampal CA1 neurons participate in dynamic ensemble codes for space and memory. Prominent features of the environment are represented by an increased density of place cells, but cellular principles governing the formation and plasticity of such disproportionate maps are unknown. We thus imaged experience-dependent long-term changes in spatial representations at the cellular level in the CA1 deep sublayer in mice learning to navigate in a virtual-reality environment. The maps were highly dynamic but gradually stabilized as over-representations for motivational (reward) and environmental (landmark) salience emerged in different time courses by selective consolidation of relevant spatial representations. Relocation of the reward extensively reorganized pre-formed maps by a mechanism involving rapid recruitment of cells from the previous location followed by their re-stabilization, indicating that a subset of neurons encode reward-related information. The distinct properties of these CA1 cells may provide a substrate by which salient experience forms lasting and adaptable memory traces.

neuroscience↗

bioRxiv2017

Disproportional distribution of radioactive elements in the marine ecosystems surrounding the accident site of the Fukushima Daiichi Nuclear Power Plant

After the Fukushima Daiichi Nuclear Power Plant accident, various surveys have been performed to measure the extent of radioactive contamination in marine sediments, surface waters, plankton, and fish. However, the radioactive contamination of one of the most important ecological niches, biofilms, has not been investigated. Therefore, in this study, we sampled biofilms from sea floor stones around Hisanohama Port, which is less than 30 km south of the accident site, and then analyzed the microbial community structure and element profiles, including those of radioactive elements, of these biofilms in order to determine the accumulation and retention of radioactive elements in them. Our results showed that the biofilm samples contained relatively high levels of radioactive cesium even when the sampling was performed 8-11 months after the accident. Our results also suggested that the structure of the biofilm organismal community is related to the element profile of radioactive cesium. Thus, our study suggests that biofilms are a possible radioactive compound accumulator in the natural environment and that they can retain radioactive material for at least 8-11 months.

ecology↗