The interferon consensus sequence binding protein (ICSBP) is an interferon regulatory transcription factor, also referred to as IRF8. ICSBP acts as a suppressor of myeloid leukemia, although few target genes explaining this effect have been identified. In the current studies, we identified the gene encoding growth arrest specific 2 (GAS2) as an ICSBP target gene relevant to leukemia suppression. We find that ICSBP, Tel, and histone deacetylase 3 (HDAC3) bind to a cis element in the GAS2 promoter and repress transcription in myeloid progenitor cells. Gas2 inhibits calpain protease activity, and -catenin is a calpain substrate in these cells. Consistent with this, ICSBP decreases -catenin protein and activity in a Gas2-and calpain-dependent manner. Conversely, decreased ICSBP expression increases -catenin protein and activity by the same mechanism. This is of interest, because decreased ICSBP expression and increased -catenin activity are associated with poor prognosis and blast crisis in chronic myeloid leukemia (CML). We find that the expression of Bcr/abl (the CML oncoprotein) increases Gas2 expression in an ICSBP-dependent manner. This results in decreased calpain activity and a consequent increase in -catenin activity in Bcr/abl-positive (Bcr/abl ؉ ) cells. Therefore, these studies have identified a Gas2/calpain-dependent mechanism by which ICSBP influences -catenin activity in myeloid leukemia.
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...
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Although the roles of Jak-Stat pathways in type I and II interferon (IFN)-dependent transcriptional regulation are well established, the precise mechanisms of mRNA translation for IFN-sensitive genes remain to be defined. We examined the effects of IFNs on the phosphorylation/activation of eukaryotic translation initiation factor 4B (eIF4B). Our data show that eIF4B is phosphorylated on Ser422 during treatment of sensitive cells with alpha IFN (IFN-␣) or IFN-␥. Such phosphorylation is regulated, in a cell type-specific manner, by either the p70 S6 kinase (S6K) or the p90 ribosomal protein S6K (RSK) and results in enhanced interaction of the protein with eIF3A (p170/eIF3A) and increased associated ATPase activity. Our data also demonstrate that IFN-inducible eIF4B activity and IFN-stimulated gene 15 protein (ISG15) or IFN-␥-inducible chemokine CXCL-10 protein expression are diminished in S6k1/S6k2 double-knockout mouse embryonic fibroblasts. In addition, IFN-␣-inducible ISG15 protein expression is blocked by eIF4B or eIF3A knockdown, establishing a requirement for these proteins in mRNA translation/protein expression by IFNs. Importantly, the generation of IFN-dependent growth inhibitory effects on primitive leukemic progenitors is dependent on activation of the S6K/eIF4B or RSK/eIF4B pathway. Taken together, our findings establish critical roles for S6K and RSK in the induction of IFN-dependent biological effects and define a key regulatory role for eIF4B as a common mediator and integrator of IFN-generated signals from these kinases.Extensive work over the years has established that the control of initiation of mRNA translation occurs primarily at the step at which the 40S ribosomal subunit is recruited to mRNA, to be positioned at the initiation codon (15). Most eukaryotic mRNAs contain a 5Ј cap structure (m7GpppN) to which the cap-binding protein complex eukaryotic initiation factor 4F (eIF4F) is attached. eIF4F is composed of three subunits: eIF4E, the cap-binding subunit; eIF4A, a protein with RNA helicase activity that unwinds the mRNA 5Ј secondary structure; and eIF4G, a scaffolding protein that associates with other IFs (15,18,20,37,54). The unphosphorylated/activated form of the translational repressor 4E-BP1 (eIF4E-binding protein 1) competes with eIF4G for binding to eIF4E and blocks cap-dependent mRNA translation (37), while such 4E-BP1-eIF4E interactions are decreased when phosphorylation of 4E-BP1 occurs by the mammalian target of rapamycin (mTOR) kinase (15,18,20,37,54). Beyond phosphorylation of 4E-BP1, mTOR regulates activation of the p70 S6 kinase (S6K), which in turn phosphorylates several substrates, including the S6 ribosomal protein (rpS6), eIF4B, and the tumor suppressor PDCD4 (13,18,20,54).Although much is known about the roles of mTOR-generated signals in the control of mRNA translation for cytokines and growth factors, the roles of various mTOR effectors in the initiation of mRNA translation in response to interferons (IFNs) remain to be precisely defined. Type I (␣, , ε, , and ) and I...
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