DNAJA1 controls the fate of misfolded mutant p53 through the mevalonate pathway

Stabilization of mutant p53 (mutp53) in tumours greatly contributes to malignant progression. However, little is known about the underlying mechanisms and therapeutic approaches to destabilize mutp53. Here, through high-throughput screening we identify statins, cholesterol-lowering drugs, as degradation inducers for conformational or misfolded p53 mutants with minimal effects on wild-type p53 (wtp53) and DNA contact mutants. Statins preferentially suppress mutp53-expressing cancer cell growth. Specific reduction of mevalonate-5-phosphate by statins or mevalonate kinase knockdown induces CHIP ubiquitin ligase-mediated nuclear export, ubiquitylation, and degradation of mutp53 by impairing interaction of mutp53 with DNAJA1, a Hsp40 family member. Knockdown of DNAJA1 also induces CHIP-mediated mutp53 degradation, while its overexpression antagonizes statin-induced mutp53 degradation. Our study reveals that DNAJA1 controls the fate of misfolded mutp53, provides insights into potential strategies to deplete mutp53 through the mevalonate pathway–DNAJA1 axis, and highlights the significance of p53 status in impacting statins’ efficacy on cancer therapy

ABSTRACT Reconsidering Wireless Systems with Multiple Radios

The tremendous popularity of wireless systems in recent years has led to the commoditization of RF transceivers (radios) whose prices have fallen dramatically. The lower cost allows us to consider using two or more radios in the same device. Given this, we argue that wireless systems that use multiple radios in a collaborative manner dramatically improve system performance and functionality over the traditional single radio wireless systems that are popular today. In this context, we revisit some standard problems in wireless networking, including energy management, capacity enhancement, mobility management, channel failure recovery, and last-hop packet scheduling. We show that a systems approach can alleviate many of the performance and robustness issues prevalent in current wireless LAN systems. We explore the implications of the multi-radio approach on software and hardware design, as well as on algorithmic and protocol research issues. We identify three key design guidelines for constructing multi-radio systems and present results from two systems that we have built. Our experience supports our position that a multi-radio platform offers significant benefits for wireless systems. 1 1

A multi-radio unification protocol for IEEE 802.11 wireless networks

We present a link layer protocol called the Multi-radio Unification Protocol or MUP. On a single node, MUP coordinates the operation of multiple wireless network cards tuned to non-overlapping frequency channels. The goal of MUP is to optimize local spectrum usage via intelligent channel selection in a multihop wireless network. MUP works with standard-compliant IEEE 802.11 hardware, does not require changes to applications or higher-level protocols, and can be deployed incrementally. The primary usage scenario for MUP is a multihop community wireless mesh network, where cost of the radios and battery consumption are not limiting factors. We describe the design and implementation of MUP, and analyze its performance using both simulations and measurements based on our implementation. Our results show that under dynamic traffic patterns with realistic topologies, MUP significantly improves both TCP throughput and user perceived latency for realistic workloads. 1

Mutant p53 Depletion by Novel Inhibitors for HSP40/J-Domain Proteins Derived from the Natural Compound Plumbagin

Accumulation of missense mutant p53 (mutp53) in cancers promotes malignant progression. DNAJA1, a member of HSP40 (also known as J-domain proteins: JDPs), is shown to prevent misfolded or conformational mutp53 from proteasomal degradation. Given frequent addiction of cancers to oncogenic mutp53, depleting mutp53 by DNAJA1 inhibition is a promising approach for cancer therapy. However, there is no clinically available inhibitor for DNAJA1. Our in silico molecular docking study with a natural compound-derived small molecule library identified a plumbagin derivative, PLIHZ (plumbagin–isoniazid analog), as a potential compound binding to the J domain of DNAJA1. PLIHZ efficiently reduced the levels of DNAJA1 and several conformational mutp53 with minimal impact on DNA contact mutp53 and wild-type p53 (wtp53). An analog, called PLTFBH, which showed a similar activity to PLIHZ in reducing DNAJA1 and mutp53 levels, inhibited migration of cancer cells specifically carrying conformational mutp53, but not DNA contact mutp53, p53 null, and wtp53, which was attenuated by depletion of DNAJA1 or mutp53. Moreover, PLTFBH reduced levels of multiple other HSP40/JDPs with tyrosine 7 (Y7) and/or tyrosine 8 (Y8) but failed to deplete DNAJA1 mutants with alanine substitution of these amino acids. Our study suggests PLTFBH as a potential inhibitor for multiple HSP40/JDPs