mTOR-generated signals play critical roles in growth of leukemic cells by controlling mRNA translation of genes that promote mitogenic responses. Despite extensive work on the functional relevance of rapamycin-sensitive mTORC1 complexes, much less is known on the roles of rapamycin-insensitive (RI) complexes, including mTORC2 and RI-mTORC1, in BCR-ABL-leukemogenesis. We provide evidence for the presence of mTORC2 complexes in BCR-ABL-transformed cells and identify phosphorylation of 4E-BP1 on Thr37∕46 and Ser65 as RI-mTORC1 signals in primary chronic myelogenous leukemia (CML) cells. Our studies establish that a unique dual mTORC2∕mTORC1 inhibitor, OSI-027, induces potent suppressive effects on primitive leukemic progenitors from CML patients and generates antileukemic responses in cells expressing the T315I-BCR-ABL mutation, which is refractory to all BCR-ABL kinase inhibitors currently in clinical use. Induction of apoptosis by OSI-027 appears to negatively correlate with induction of autophagy in some types of BCR-ABL transformed cells, as shown by the induction of autophagy during OSI-027-treatment and the potentiation of apoptosis by concomitant inhibition of such autophagy. Altogether, our studies establish critical roles for mTORC2 and RI-mTORC1 complexes in survival and growth of BCR-ABL cells and suggest that dual therapeutic targeting of such complexes may provide an approach to overcome leukemic cell resistance in CML and Phþ ALL.mRNA translation | cell proliferation | cellular signaling | kinase | OSI-027
IFN␣ exerts potent inhibitory activities against malignant melanoma cells in vitro and in vivo, but the mechanisms by which it generates its antitumor effects remain unknown. We examined the effects of interferon ␣ (IFN␣) on the expression of human members of the Schlafen (SLFN) family of genes, a group of cell cycle regulators that mediate growth-inhibitory responses. Using quantitative RT-real time PCR, we found detectable basal expression of all the different human SLFN genes examined (SLFN5, SLFN11, SLFN12, SLFN13, and SLFN14), in malignant melanoma cells and primary normal human melanocytes, but SLFN5 basal expression was suppressed in all analyzed melanoma cell lines. Treatment of melanoma cells with IFN␣ resulted in induction of expression of SLFN5 in malignant cells, suggesting a potential involvement of this gene in the antitumor effects of IFN␣. Importantly, stable knockdown of SLFN5 in malignant melanoma cells resulted in increased anchorage-independent growth, as evidenced by enhanced colony formation in soft agar assays. Moreover, SLFN5 knockdown also resulted in increased invasion in three-dimensional collagen, suggesting a dual role for SLFN5 in the regulation of invasion and anchorage-independent growth of melanoma cells. Altogether, our findings suggest an important role for the SLFN family of proteins in the generation of the anti-melanoma effects of IFN␣ and for the first time directly implicate a member of the human SLFN family in the regulation of cell invasion.The interferons (IFNs) are cytokines with important pleiotropic biological effects, including generation of antitumor responses and antiviral activities (1-3). The ability of IFNs to induce antitumor responses in selective systems is highly relevant and, over the years, has had a major impact in the management of certain leukemias and solid tumors in humans. Malignant melanoma is one of the most IFN-sensitive solid tumors. There has been extensive clinical evidence on the ability of IFN␣ to generate antitumor effects in vitro in subset groups of patients with advanced metastatic malignant melanoma (4 -7), and IFN␣ is now a Food and Drug Administration-approved agent for the treatment of this malignancy. An important outstanding issue in the IFN research field has been the identification of specific mechanisms that account for differential sensitivity to the effects of IFNs. Despite the advances in the IFN-signaling field over the last 2 decades, the precise mechanisms and specific signals that account for the unique IFN sensitivity that some tumors exhibit remain largely unknown.It is now well established that IFNs regulate transcription of target genes with important functional relevance via engagement of the JAK-STAT pathway (8 -11). In recent years, additional levels of cellular regulation of IFN-inducible genes and their products have been identified, such as involvement of members of the PKC family (12-16), the MAPK cascades (17-22), translational regulation via mammalian target of rapamycin and 4EBP1 (23-28), modulation of histo...
Shigella, the causative agent of bacillary dysentery in humans, invades epithelial cells, using a type III secretory system (T3SS) to inject bacterial effectors into host cells and remodel the actin cytoskeleton. ATP released through connexin hemichanels on the epithelial membrane stimulates Shigella invasion and dissemination in epithelial cells. Here, we show that prior to contact with the cell body, Shigella is captured by nanometer-thin micropodial extensions (NMEs) at a distance from the cell surface, in a process involving the T3SS tip complex proteins and stimulated by ATP- and connexin-mediated signaling. Upon bacterial contact, NMEs retract, bringing bacteria in contact with the cell body, where invasion occurs. ATP stimulates Erk1/2 activation, which controls actin retrograde flow in NMEs and their retraction. These findings reveal previously unappreciated facets of interaction of an invasive bacterium with host cells and a prominent role for Erk1/2 in the control of filopodial dynamics.
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