During apoptosis, phosphatidylserine, which is normally restricted to the inner leaflet of the plasma membrane, is exposed on the surface of apoptotic cells and has been suggested to act as an "eat-me" signal to trigger phagocytosis. It is unclear how phagocytes recognize phosphatidylserine. Recently, a putative phosphatidylserine receptor (PSR) was identified and proposed to mediate recognition of phosphatidylserine and phagocytosis. We report that psr-1, the Caenorhabditis elegans homolog of PSR, is important for cell corpse engulfment. In vitro PSR-1 binds preferentially phosphatidylserine or cells with exposed phosphatidylserine. In C. elegans, PSR-1 acts in the same cell corpse engulfment pathway mediated by intracellular signaling molecules CED-2 (homologous to the human CrkII protein), CED-5 (DOCK180), CED-10 (Rac GTPase), and CED-12 (ELMO), possibly through direct interaction with CED-5 and CED-12. Our findings suggest that PSR-1 is likely an upstream receptor for the signaling pathway containing CED-2, CED-5, CED-10, and CED-12 proteins and plays an important role in recognizing phosphatidylserine during phagocytosis.

A prominent feature of most if not all cancers is a striking genetic instability, leading to ongoing accrual of mutational changes, some of which underlie tumor progression, including acquisition of invasiveness, drug resistance, and metastasis. Thus, the molecular basis for the generation of this genetic diversity in cancer cells has important implications in understanding cancer progression. Here we report that homologous recombination (HR) activity is elevated in multiple myeloma (MM) cells and leads to an increased rate of mutation and progressive accumulation of genetic variation over time. We demonstrate that the inhibition of HR activity in MM cells by small inhibitory RNA (siRNAs) targeting recombinase leads to significant reduction in the acquisition of new genetic changes in the ge- IntroductionGenetic changes observed at the chromosomal level or at the nucleotide sequence level are associated with the development and progression of malignant phenotypes. Although some specific cancers are associated with and attributed to specific cytogenetic and molecular aberrations, for example, chronic myelogenous leukemia or acute promyelocytic leukemia, the majority of cancers display a complex spectra of diverse genetic alterations apparent at diagnosis and acquire additional changes with progression of the disease. 1 Because the large-scale chromosomal alterations that arise frequently in cancer cells occur infrequently in normal cells, [2][3][4] it implies that the control mechanisms that maintain the integrity of chromosomes in normal cells are disrupted in cancer cells.A variety of intrinsic or extrinsic chemical as well as physical factors damage DNA in living organisms which, if not repaired, can lead to mutations and cellular transformation. The best known machinery involved in repairing potentially lethal DNA damage, especially double-strand breaks, is genetic recombination. 5 In fact the repair of DNA lesions may account for majority of the recombination occurring in mitosis. 6 Recombination plays an important role in maintaining the genetic integrity of a cell, including DNA repair 7 and proper segregation of chromosomes in meiosis. 8 In the normal cellular environment, recombination-associated proteins are highly regulated, precise, and exhibit considerable specificity for DNA sequences, which have either an extensive homology or a characteristic signal sequence. However, with its significant ability to modify DNA, if dysregulated, it can lead to genomic instability. Recombination can be induced by several chemicals, radiation, and oncogenic viruses. [9][10][11][12][13][14] The induction or overexpression of a recombination pathway may result in DNA rearrangements, leading to oncogene activation 15 and/or the loss of hemizygous functional alleles of tumor suppressor genes.Aberrant or dysregulated recombination has been implicated in chromosome translocation, 9,16,17 gene amplification, 18 and telomere maintenance 19 and may therefore underlie the chromosomal aberrations observed with high frequency i...

The combination of in vitro and in vivo studies presented here identify two evolutionarily conserved players in engulfment, TRIO/UNC73 and RhoG/MIG-2, and the TRIO --> RhoG signaling module is linked by ELMO/CED-12 to Dock180-dependent Rac activation during engulfment. This work also identifies ARM repeats within CED-12/ELMO and their role in linking RhoG and Rac, two GTPases that function in tandem during engulfment.

Purpose: The aim of this study was to test the efficacy of telomestatin, an intramolecular G-quadruplex intercalating drug with specificity for telomeric sequences, as a potential therapeutic agent for multiple myeloma.Experimental Design: We treated ARD, ARP, and MM1S myeloma cells with various concentrations of telomestatin for 7 days and evaluated for telomerase activity. Myeloma cells were treated with the minimal effective telomestatin concentration for 3-5 weeks. Every 7 th day the fraction of live cells was determined by trypan blue exclusion, aliquots of cells were removed for various molecular assays, and the remaining cells were replated at the same cell number and at the same concentration of telomestatin. Telomere length, apoptosis, and gene expression changes were monitored as described in detail in "Materials and Methods."Results: Telomestatin treatment led to inhibition of telomerase activity, reduction in telomere length, and apoptotic cell death in ARD, MM1S, and ARP myeloma cells. Gene expression profile after 1 and 7 days of telomestatin treatment revealed >2-fold change in only 6 (0.027%) and 51 (0.23%) of 33,000 genes surveyed, respectively. No changes were seen in expression of genes involved in cell cycle, apoptosis, DNA repair, or recombination.Conclusions: These results demonstrate that telomestatin exerts its antiproliferative and proapoptotic effects in myeloma cells via inhibition of telomerase and subsequent reduction in telomere length. We conclude that telomerase is an important potential therapeutic target for multiple myeloma therapy, and G-quadruplex interacting agents with specificity for binding to telomeric sequences can be important agents for additional evaluation.