SUMMARY The JAK2V617F constitutively activated tyrosine kinase is found in most patients with myeloproliferative neoplasms. While examining the interaction between JAK2 and PRMT5, an arginine methyltransferase originally identified as JAK2 binding protein 1, we found that JAK2V617F (and JAK2K539L) bound PRMT5 more strongly than did wild-type JAK2. These oncogenic kinases also acquired the ability to phosphorylate PRMT5, greatly impairing its ability to methylate its histone substrates, and representing a specific gain-of-function that allows them to regulate chromatin modifications. We readily detected PRMT5 phosphorylation in JAK2V617F-positive patient samples and when we knocked down PRMT5 in human CD34+ cells using shRNA, we observed increased colony formation and erythroid differentiation. These results indicate that phosphorylation of PRMT5 contributes to the mutant JAK2-induced myeloproliferative phenotype.

Calcium is a versatile and dynamic 2nd messenger that is essential for the survival of all higher organisms. In cells that undergo activation or excitation, calcium is released from the endoplasmic/sarcoplasmic reticulum to activate calcium-dependent kinases and phosphatases, thereby regulating numerous cellular processes; for example, apoptosis and autophagy. In the case of apoptosis, endogenous ligands or pharmacological agents induce prolonged cytosolic calcium elevation, which in turn leads to cell death. In contrast, there is now evidence that calcium regulates autophagy by several mechanisms, and these may be important for maintaining cell survival. Here we summarize what is known about how calcium regulates these life and death decisions. We pay particular attention to pathways that have been described in lymphocytes and cardiomyocytes, as these systems provide optimal models for understanding calcium signaling in the context of normal cell physiology.

IntroductionThe Bcl-2 protein contributes to the pathophysiology of cancer and the resistance of cancer to therapeutic agents by virtue of its ability to inhibit apoptosis. 1,2 The Bcl-2-positive lymphoid malignancies follicular lymphoma and chronic lymphocytic leukemia (CLL) are prime examples. They are associated with an elevation of Bcl-2 because of the t(14;18) chromosomal translocation in follicular lymphoma 3 and the loss of miR-15a and miR16-1 in CLL. 4,5 Cure of these malignancies is infrequently achieved with current therapeutic modalities, and thus a major challenge remains to develop new treatment modalities based on an understanding of the fundamental disease mechanisms. 6 Bcl-2 blocks apoptosis in part by binding its proapoptotic relatives, thus preserving mitochondrial integrity and preventing cytochrome c release. 7,8 Therefore, considerable investment has been made in the development of novel therapeutic agents, such as , that disrupt the inhibitory interaction of Bcl-2 with its proapoptotic relatives. 1,2,9-11 Several of these agents are currently undergoing clinical testing. However, Bcl-2 also inhibits apoptosis by regulating the release of Ca 2ϩ from the endoplasmic reticulum (ER). [12][13][14] This recently characterized mechanism involves a physical interaction of Bcl-2 with the inositol 1,4,5-trisphosphate receptor (IP 3 R) Ca 2ϩ -release channel on the ER. Through this interaction, Bcl-2 prevents cytoplasmic Ca 2ϩ elevation sufficient to trigger apoptosis. However, the potential contribution of the Bcl-2-IP 3 R interaction to the survival of CLL has not been investigated, so the opportunity for targeting this interaction therapeutically has not yet been realized.The IP 3 R is an IP 3 -gated Ca 2ϩ channel that is highly conserved, represented by 3 isoforms, and present in virtually all cell types. 15,16 IP 3 -dependent release of Ca 2ϩ from the ER into the cytoplasm produces Ca 2ϩ signals, generally in the form of Ca 2ϩ oscillations, which govern diverse cellular functions including cell proliferation and survival. 17,18 Ca 2ϩ oscillations support cell survival in part by positively regulating mitochondrial metabolism, but sustained high-amplitude elevations of Ca 2ϩ induce mitochondrial Ca 2ϩ overload and apoptosis. [19][20][21] Bcl-2 inhibits high-amplitude, proapoptotic Ca 2ϩ elevation but does not interfere with physiologic Ca 2ϩ oscillations. 22 In fact, under certain circumstances Bcl-2 and its homolog Bcl-xl enhance Ca 2ϩ oscillations, [22][23][24][25][26] and through this mechanism are predicted to promote efficient mitochondrial bioenergetics. 27 Thus, Bcl-2 supports cell survival both by enhancing physiologic Ca 2ϩ signals and by blocking proapoptotic Ca 2ϩ elevation.A major focus of our work has been to understand how Bcl-2 inhibits proapoptotic elevation of Ca 2ϩ based on evidence that Bcl-2 binds to the IP 3 R and thus inhibits ER Ca 2ϩ release. [28][29][30][31][32] Although this interaction has been mainly detected in cell extracts by coimmunoprecipitation or blue native gel ...

This paper characterizes the actual science performance of the James Webb Space Telescope (JWST), as determined from the six month commissioning period. We summarize the performance of the spacecraft, telescope, science instruments, and ground system, with an emphasis on differences from pre-launch expectations. Commissioning has made clear that JWST is fully capable of achieving the discoveries for which it was built. Moreover, almost across the board, the science performance of JWST is better than expected; in most cases, JWST will go deeper faster than expected. The telescope and instrument suite have demonstrated the sensitivity, stability, image quality, and spectral range that are necessary to transform our understanding of the cosmos through observations spanning from near-earth asteroids to the most distant galaxies.