Identification of Novel Regulatory and Target Proteins in the p53 Pathway: APC2 and PFK2

The Mdm2 proto-oncoprotein is the primary negative regulator for the tumor suppressor p53. While it is believed that Mdm2 degradation is regulated via its own E3 ubiquitin ligase activity, recent development of knock-in mouse models demonstrate that in vivo Mdm2 E3 ligase function is dispensable for the degradation of Mdm2 itself. Here, we show that the anaphase promoting complex/cyclosome (APC/C) is an E3 ubiquitin ligase for Mdm2 degradation. We demonstrate that APC2, a scaffold subunit of APC/C, binds to Mdm2 and is required for Mdm2 polyubiquitination and proteasomal degradation. Downregulation of APC2 by RNAi results in transcription-independent accumulation of Mdm2 and attenuation of stress-induced p53 stabilization, leading to decreased senescence and increased cell survival. Furthermore, APC2 expression is frequently downregulated in human cancers and in tumor cell lines, and often correlates with Mdm2 overexpression. Our study shows the regulation of Mdm2 by APC/C E3 ubiquitin ligase, modifying our understanding of Mdm2 degradation in vivo, and providing important therapeutic implications for tumors with Mdm2 overexpression. Although nucleotide shortage can result in genomic instability and cancer development, relatively little is known regarding the mechanisms responsible for coordinating nucleotide shortage and cell metabolism to maintain a nucleotide pool amenable to DNA replication and DNA damage repair. Here, we provide evidence supporting a model whereby p53-dependent regulation of phosphofructokinase-2 (PFK2) is essential for the redirection of glucose from glycolysis to the pentose phosphate pathway (PPP) under nucleotide shortage stress. Our data show that the suppression of PFK2 is specific to nucleotide shortage. Decreased expression of PFK2 resulted in a decrease in the rate of glycolysis and an increase in PPP activity, leading to an increased nucleotide pool and improved DNA damage repair efficiency. Importantly, exogenously supplied nucleosides effectively rescued the DNA damage repair defect caused by p53 inactivation, further suggesting that the maintenance of the nucleotide pool is an important function of p53. These findings underscore an essential role for p53 in modulating glucose metabolism in response to nucleotide shortage stress, and suggest that the tumor suppressive function of p53 is linked to its role in responding to nucleotide shortage and coordinating metabolic adaptation.Doctor of Philosoph

Mutual Information-Based Integrated Sensing and Communications: A WMMSE Framework

In this letter, a weighted minimum mean square error (WMMSE) empowered integrated sensing and communication (ISAC) system is investigated. One transmitting base station and one receiving wireless access point are considered to serve multiple users a sensing target. Based on the theory of mutual-information (MI), communication MI and sensing MI rate are utilized as the performance metrics under the presence of clutters. In particular, we propose an novel MI-based WMMSE-ISAC method by developing a unique transceiver design mechanism to maximize the weighted sensing and communication sum-rate of this system. Such a maximization process is achieved by utilizing the classical method -- WMMSE, aiming to better manage the effect of sensing clutters and the interference among users. Numerical results show the effectiveness of our proposed method, and the performance trade-off between sensing and communication is also validated

Identification of microRNA precursors based on random forest with network-level representation method of stem-loop structure

<p>Abstract</p> <p>Background</p> <p>MicroRNAs (miRNAs) play a key role in regulating various biological processes such as participating in the post-transcriptional pathway and affecting the stability and/or the translation of mRNA. Current methods have extracted feature information at different levels, among which the characteristic stem-loop structure makes the greatest contribution to the prediction of putative miRNA precursor (pre-miRNA). We find that none of these features alone is capable of identifying new pre-miRNA accurately.</p> <p>Results</p> <p>In the present work, a pre-miRNA stem-loop secondary structure is translated to a network, which provides a novel perspective for its structural analysis. Network parameters are used to construct prediction model, achieving an area under the receiver operating curves (AUC) value of 0.956. Moreover, by repeating the same method on two independent datasets, accuracies of 0.976 and 0.913 are achieved, respectively.</p> <p>Conclusions</p> <p>Network parameters effectively characterize pre-miRNA secondary structure, which improves our prediction model in both prediction ability and computation efficiency. Additionally, as a complement to feature extraction methods in previous studies, these multifaceted features can reflect natural properties of miRNAs and be used for comprehensive and systematic analysis on miRNA.</p

Progressive Conservative Adaptation for Evolving Target Domains

Conventional domain adaptation typically transfers knowledge from a source domain to a stationary target domain. However, in many real-world cases, target data usually emerge sequentially and have continuously evolving distributions. Restoring and adapting to such target data results in escalating computational and resource consumption over time. Hence, it is vital to devise algorithms to address the evolving domain adaptation (EDA) problem, \emph{i.e.,} adapting models to evolving target domains without access to historic target domains. To achieve this goal, we propose a simple yet effective approach, termed progressive conservative adaptation (PCAda). To manage new target data that diverges from previous distributions, we fine-tune the classifier head based on the progressively updated class prototypes. Moreover, as adjusting to the most recent target domain can interfere with the features learned from previous target domains, we develop a conservative sparse attention mechanism. This mechanism restricts feature adaptation within essential dimensions, thus easing the inference related to historical knowledge. The proposed PCAda is implemented with a meta-learning framework, which achieves the fast adaptation of the classifier with the help of the progressively updated class prototypes in the inner loop and learns a generalized feature without severely interfering with the historic knowledge via the conservative sparse attention in the outer loop. Experiments on Rotated MNIST, Caltran, and Portraits datasets demonstrate the effectiveness of our method.Comment: 7 pages, 5 figure

DetToolChain: a new prompting paradigm to unleash detection ability of MLLM

We present DetToolChain, a novel prompting paradigm, to unleash the zero-shot object detection ability of multimodal large language models (MLLMs), such as GPT-4V and Gemini. Our approach consists of a detection prompting toolkit inspired by high-precision detection priors and a new Chain-of-Thought to implement these prompts. Specifically, the prompts in the toolkit are designed to guide the MLLM to focus on regional information (e.g., zooming in), read coordinates according to measure standards (e.g., overlaying rulers and compasses), and infer from the contextual information (e.g., overlaying scene graphs). Building upon these tools, the new detection chain-of-thought can automatically decompose the task into simple subtasks, diagnose the predictions, and plan for progressive box refinements. The effectiveness of our framework is demonstrated across a spectrum of detection tasks, especially hard cases. Compared to existing state-of-the-art methods, GPT4V with our DetToolChain improves state-of-the-art object detectors by +21.5% AP50 on MS COCO Novel class set for open-vocabulary detection, +24.23% Acc on RefCOCO val set for zero-shot referring expression comprehension, +14.5% AP on D-cube describe object detection FULL setting

Identification of LIMK2 as a therapeutic target in castration resistant prostate cancer

This study identified LIMK2 kinase as a disease-specific target in castration resistant prostate cancer (CRPC) pathogenesis, which is upregulated in response to androgen deprivation therapy, the current standard of treatment for prostate cancer. Surgical castration increases LIMK2 expression in mouse prostates due to increased hypoxia. Similarly, human clinical specimens showed highest LIMK2 levels in CRPC tissues compared to other stages, while minimal LIMK2 was observed in normal prostates. Most notably, inducible knockdown of LIMK2 fully reverses CRPC tumorigenesis in castrated mice, underscoring its potential as a clinical target for CRPC. We also identified TWIST1 as a direct substrate of LIMK2, which uncovered the molecular mechanism of LIMK2-induced malignancy. TWIST1 is strongly associated with CRPC initiation, progression and poor prognosis. LIMK2 increases TWIST1 mRNA levels upon hypoxia; and stabilizes TWIST1 by direct phosphorylation. TWIST1 also stabilizes LIMK2 by inhibiting its ubiquitylation. Phosphorylation-dead TWIST1 acts as dominant negative and fully prevents EMT and tumor formation in vivo, thereby highlighting the significance of LIMK2-TWIST1 signaling axis in CRPC. As LIMK2 null mice are viable, targeting LIMK2 should have minimal collateral toxicity, thereby improving the overall survival of CRPC patients

p53 coordinates DNA repair with nucleotide synthesis by suppressing PFKFB3 expression and promoting the pentose phosphate pathway

Activation of p53 in response to DNA damage is essential for tumor suppression. Although previous studies have emphasized the importance of p53-dependent cell cycle arrest and apoptosis for tumor suppression, recent studies have suggested that other areas of p53 regulation, such as metabolism and DNA damage repair (DDR), are also essential for p53-dependent tumor suppression. However, the intrinsic connections between p53-mediated DDR and metabolic regulation remain incompletely understood. Here, we present data suggesting that p53 promotes nucleotide biosynthesis in response to DNA damage by repressing the expression of the phosphofructokinase-2 (PFK2) isoform 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), a rate-limiting enzyme that promotes glycolysis. PFKFB3 suppression increases the flux of glucose through the pentose phosphate pathway (PPP) to increase nucleotide production, which results in more efficient DNA damage repair and increased cell survival. Interestingly, although p53-mediated suppression of PFKFB3 could increase the two major PPP products, NADPH and nucleotides, only nucleotide production was essential to promote DDR. By identifying the novel p53 target PFKFB3, we report an important mechanistic connection between p53-regulated metabolism and DDR, both of which play crucial roles in tumor suppression