E3 Ubiquitin Ligases in Cancer and Their Pharmacological Targeting

Ubiquitination plays many critical roles in protein function and regulation. Consequently, mutation and aberrant expression of E3 ubiquitin ligases can drive cancer progression. Identifying key ligase-substrate relationships is crucial to understanding the molecular basis and pathways behind cancer and toward identifying novel targets for cancer therapeutics. Here, we review the importance of E3 ligases in the regulating the hallmarks of cancer, discuss some of the key and novel E3 ubiquitin ligases that drive tumor formation and angiogenesis, and review the clinical development of inhibitors that antagonize their function. We conclude with perspectives on the field and future directions toward understanding ubiquitination and cancer progression

Structural and molecular basis of the assembly of the TRPP2/PKD1 complex

Mutations in PKD1 and TRPP2 account for nearly all cases of autosomal dominant polycystic kidney disease (ADPKD). These 2 proteins form a receptor/ion channel complex on the cell surface. Using a combination of biochemistry, crystallography, and a single-molecule method to determine the subunit composition of proteins in the plasma membrane of live cells, we find that this complex contains 3 TRPP2 and 1 PKD1. A newly identified coiled-coil domain in the C terminus of TRPP2 is critical for the formation of this complex. This coiled-coil domain forms a homotrimer, in both solution and crystal structure, and binds to a single coiled-coil domain in the C terminus of PKD1. Mutations that disrupt the TRPP2 coiled-coil domain trimer abolish the assembly of both the full-length TRPP2 trimer and the TRPP2/PKD1 complex and diminish the surface expression of both proteins. These results have significant implications for the assembly, regulation, and function of the TRPP2/PKD1 complex and the pathogenic mechanism of some ADPKD-producing mutations

Fermi Surface reconstruction in the CDW state of CeTe3 observed by photoemission

CeTe3 is a layered compound where an incommensurate Charge Density Wave (CDW) opens a large gap (400 meV) in optimally nested regions of the Fermi Surface (FS), whereas other sections with poorer nesting remain ungapped. Through Angle-Resolved Photoemission, we identify bands backfolded according to the CDW periodicity. They define FS pockets formed by the intersection of the original FS and its CDW replica. Such pockets illustrate very directly the role of nesting in the CDW formation but they could not be detected so far in a CDW system. We address the reasons for the weak intensity of the folded bands, by comparing different foldings coexisting in CeTe3

In-plane thermal conductivity of large single crystals of Sm-substituted (Y1−x_{1-x}Smx_{x})Ba2_{2}Cu3_{3}O7−δ_{7-\delta}

We have investigated the in-plane thermal conductivity $\kappa_{ab}(T,H)$ of large single crystals of optimally oxygen-doped (Y$_{1-x}$,Sm$_{x}$)Ba$_{2}$Cu$_{3}$O$_{7-\delta}$ ($x$=0, 0.1, 0.2 and 1.0) and YBa$_{2}$(Cu$_{1-y}$Zn$_{y}$)$_{3}$O$_{7-\delta}$($y$=0.0071) as functions of temperature and magnetic field (along the c axis). For comparison, the temperature dependence of $\kappa_{ab}$ for as-grown crystals with the corresponding compositions are presented. The nonlinear field dependence of $\kappa_{ab}$ for all crystals was observed at relatively low fields near a half of $T_{c}$. We make fits of the $\kappa(H)$ data to an electron contribution model, providing both the mean free path of quasiparticles $\ell_{0}$ and the electronic thermal conductivity $\kappa_{e}$, in the absence of field. The local lattice distortion due to the Sm substitution for Y suppresses both the phonon and electron contributions. On the other hand, the light Zn doping into the CuO $_{2}$ planes affects solely the electron component below $T_{c}$, resulting in a substantial decrease in $\ell_{0}$ .Comment: 7 pages,4 figures,1 tabl

The onset of the vortex-like Nernst signal above Tc in La_{2-x}Sr_xCuO_4 and Bi_2Sr_{2-y}La_yCuO_6

The diffusion of vortices down a thermal gradient produces a Josephson signal which is detected as the vortex Nernst effect. In a recent report, Xu et al., Nature 406, 486 (2000), an enhanced Nernst signal identified with vortex-like excitations was observed in a series of La_{2-x}Sr_xCuO_4 (LSCO) crystals at temperatures 50-100 K above T_c. To pin down the onset temperature T_{\nu} of the vortex-like signal in the lightly doped regime (0.03 < x < 0.07), we have re-analyzed in detail the carrier contribution to the Nernst signal. By supplementing new Nernst measurements with thermopower and Hall-angle data, we isolate the off-diagonal Peltier conductivity \alpha_{xy} and show that its profile provides an objective determination of T_{\nu}. With the new results, we revise the phase diagram for the fluctuation regime in LSCO to accomodate the lightly doped regime. In the cuprate Bi_2Sr_{2-y}La_yCuO_6, we find that the carrier contribution is virtually negligible for y in the range 0.4-0.6. The evidence for an extended temperature interval with vortex-like excitations is even stronger in this system. Finally, we discuss how T_{\nu} relates to the pseudogap temperature T* and the implications of strong fluctuations between the pseudogap state and the d-wave superconducting state.Comment: 10 pages, 10 figure

Nernst Effect and Superconducting Fluctuations in Zn-doped YBa2_{2}Cu3_{3}O7−δ_{7-\delta}

We report the measurements of in-plane resistivity, Hall effect, and Nernst effect in Zn doped YBa$_{2}$Cu$_{3}$O$_{7-\delta}$ epitaxial thin films grown by pulsed laser deposition technique. The pseudogap temperature, $T^*$, determined from the temperature dependence of resistivity, does not change significantly with Zn doping. Meanwhile the onset temperature ($T^{\nu}$) of anomalous Nernst signal above $T_{c0}$, which is interpreted as evidence for vortex-like excitations, decreases sharply as the superconducting transition temperature $T_{c0}$ does. A significant decrease in the maximum of vortex Nernst signal in mixed state is also observed, which is consistent with the scenario that Zn impurities cause a decrease in the superfluid density and therefore suppress the superconductivity. The phase diagram of $T^*$, $T^{\nu}$, and $T_{c0}$ versus Zn content is presented and discussed.Comment: 6 pages, 5 figures, Latex; v2: to be published in PR