The cytosolic 185 and 210 kDa Bcr‐Abl protein tyrosine kinases play important roles in the development of Philadelphia chromosome positive (Ph+) chronic myelogenous leukemia (CML) and acute lymphoblastic leukemia (Ph+ ALL). p185 and p210 Bcr‐Abl contain identical abl‐encoded sequences juxtaposed to a variable number of bcr‐derived amino acids. As the mitogenic and transforming activities of tyrosine kinases involve stimulation of the Ras pathway, we analyzed Bcr‐Abl oncoproteins for interactions with cytoplasmic proteins that mediate Ras activation. Such polypeptides include Grb2, which comprises a single Src homology 2 (SH2) domain flanked by two SH3 domains, and the 66, 52 and 46 kDa Shc proteins which possess an SH2 domain in their carboxy‐terminus. Grb2 associates with tyrosine phosphorylated proteins through its SH2 domain, and with the Ras guanine nucleotide releasing protein mSos1 through its SH3 domains. mSos1 stimulates conversion of the inactive GDP‐bound form of Ras to the active GTP‐bound state. In bcr‐abl‐transformed cells, Grb2 and mSos1 formed a physical complex with Bcr‐Abl. In vitro, the Grb2 SH2 domain bound Bcr‐Abl through recognition of a tyrosine phosphorylation site within the amino‐terminal bcr‐encoded sequence (p.Tyr177‐Val‐Asn‐Val), that is common to both Bcr‐Abl proteins. These results suggest that autophosphorylation within the Bcr element of Bcr‐Abl creates a direct physical link to Grb2‐mSos1, and potentially to the Ras pathway, and thereby modifies the target specificity of the Abl tyrosine kinase.(ABSTRACT TRUNCATED AT 250 WORDS)

Preferential oxidation of CO (PROX) in H2-rich stream is critical to the production of clean H2 for the H2-based fuel cells, which provide clean and efficient energy conversion. Development of highly active and selective PROX catalysts is highly desirable but proved to be extremely challenging. Here we report that CeO2-supported Au single atoms (Au1/CeO2) are highly active, selective, and extremely stable for PROX at the PEMFC working temperature (∼80 °C) with >99.5% CO conversion over a wide temperature window, 70–120 °C (or 50–100 °C, depending on the Au loading). The high CO conversion realized at high temperatures is attributed to the unique property of single-atom catalysts that is unable to dissociatively adsorb H2 and thus has a low reactivity toward H2 oxidation. This strategy is proven in general and can be extended to other oxide-supported Au atoms (e.g., Au1/FeO x ), which may open a new window for the efficient catalysis of the PROX reaction.

We have previously reported that the Jak2 tyrosine kinase but not Jak1 is tyrosine phosphorylated in the absence of IL-3 in Bcr ± Abl positive M3.16 cells, which are rendered IL-3 independent by BCR ± ABL gene expression. We have explored the involvement of Jak2 tyrosine phosphorylation in Bcr-Abl oncogenic eects. Our results indicate that Jak2 became tyrosine-phosphorylated in a number of cell lines expressing Bcr ± Abl, when maintained in medium lacking IL-3, whereas Bcr ± Abl negative cells lacked Jak2 tyrosine phosphorylation. Jak2 was poorly tyrosine-phosphorylated in cells expressing the SH2 deletion mutant of Bcr ± Abl compared to either wild-type Bcr ± Abl or its SH3 deletion mutant. Moreover, tyrosine phosphorylation of Jak2 by Bcr ± Abl was inhibited by the Abl tyrosine kinase inhibitor, STI 571, in a dose-dependent manner. This inhibition of Bcr ± Abl kinase by the drug did not interfere with the ability of Jak2 and Bcr ± Abl to form a complex. Studies with deletion mutants of Bcr ± Abl indicated that the Cterminal domain of Abl within Bcr ± Abl was involved in complex formation with Jak2. Similarly, GST ± Abl pulldown assays con®rmed the strong binding to Jak2 by the C-terminus of Abl. Jak2 peptide substrate studies indicated that the Bcr ± Abl and Abl tyrosine kinases speci®cally phosphorylated Y1007 of Jak2 but only poorly phosphorylated Y1008. Phosphorylation of Y1007 of Jak2 is known to be critical for its tyrosine kinase activation. Tyrosine residue 1007 of Jak2 was phosphorylated in 32Dp210 cells as measured by Western blotting with a phosphotyrosine 1007 sequence-speci®c antibody. A kinase-inactive Jak2 mutant blocked the colony forming ability of K562 cells. Tumor formation of K562 cells in nude mice was similarly inhibited by this kinase-inactive Jak2 mutant. This inhibition was independent of Stat5 tyrosine phosphorylation. Furthermore, tyrosine-phosphorylated Jak2 was detected in blood cells from CML patients in blast crisis but not in a normal marrow sample. In summary, these ®ndings provide strong evidence that the Jak2 tyrosine kinase is a critical factor in Bcr ± Abl malignant transformation. Oncogene (2001) 20, 6188 ± 6195.

Smart magnetic resonance (MR) contrast agents, by which MR contrast can be selectively enhanced under acidic tumor microenvironment, are anticipated to significantly improve the diagnostic accuracy. Here, we report pH-sensitive iron oxide nanoparticle assemblies (IONAs) that are cross-linked by small-molecular aldehyde derivative ligands. The dynamic formation and cleavage of hydrazone linkages in neutral and acidic environments, respectively, allow the reversible response of the nanoassemblies to pH variations. At neutral pH, IONAs are structurally robust due to the cross-linking by the strong hydrazone bonds. In acidic tumor microenvironment, the hydrazone bonds are cleaved so that the IONAs are quickly disassembled into a large number of hydrophilic extremely small-sized iron oxide nanoparticles (ESIONs). As a result, significantly enhanced T1MR contrast is achieved, as confirmed by the measurement of r1 values at different pH conditions. Such acidity-targeting MR signal amplification by the pH-sensitive IONAs was further validated in vivo, demonstrating a novel T1 magnetic resonance imaging (MRI) strategy for highly sensitive imaging of acidic tumors.