Author Correction: ZSCAN10 expression corrects the genomic instability of iPSCs from aged donors.

In the version of this Article originally published, Supplementary Fig. 6j showed incorrect values for the LS and AG4 glutathione samples, and Fig. 5c and Supplementary Fig.

ZSCAN10 expression corrects the genomic instability of iPSCs from aged donors.

Induced pluripotent stem cells (iPSCs), which are used to produce transplantable tissues, may particularly benefit older patients, who are more likely to suffer from degenerative diseases. However, iPSCs generated from aged donors (A-iPSCs) exhibit higher genomic instability, defects in apoptosis and a blunted DNA damage response compared with iPSCs generated from younger donors. We demonstrated that A-iPSCs exhibit excessive glutathione-mediated reactive oxygen species (ROS) scavenging activity, which blocks the DNA damage response and apoptosis and permits survival of cells with genomic instability.

Anticancer drug bortezomib increases interleukin-8 expression in human monocytes.

Bortezomib (BZ) is the first clinically approved proteasome inhibitor that has shown remarkable anticancer activity in patients with hematological malignancies. However, many patients relapse and develop resistance; yet, the molecular mechanisms of BZ resistance are not fully understood. We have recently shown that in solid tumors, BZ unexpectedly increases expression of the pro-inflammatory and pro-angiogenic chemokine interleukin-8 (IL-8), while it inhibits expression of other NFκB-regulated genes.

Bortezomib inhibits expression of TGF-β1, IL-10, and CXCR4, resulting in decreased survival and migration of cutaneous T cell lymphoma cells.

Increased expression of the immunosuppressive cytokines, TGF-β1 and IL-10, is a hallmark of the advanced stages of cutaneous T cell lymphoma (CTCL), where it has been associated with suppressed immunity, increased susceptibility to infections, and diminished antitumor responses. Yet, little is known about the transcriptional regulation of TGF-β1 and IL-10 in CTCL, and about their function in regulating the CTCL cell responses. In this article, we show that TGF-β1 and IL-10 expression in CTCL cells is regulated by NF-κB and suppressed by bortezomib (BZ), which has shown promising results in the treatment of CTCL.

Bcl3 regulates pro-survival and pro-inflammatory gene expression in cutaneous T-cell lymphoma.

The advanced stages of cutaneous T cell lymphoma (CTCL) are characterized not only by decreased levels of pro-inflammatory cytokines, resulting in high susceptibility to infections, but also by high constitutive activity of NFκB, which promotes cell survival and resistance to apoptosis. The increased expression of the proto-oncogene Bcl3 belonging to IκB family is associated with the pathogenesis of the different types of human cancer, yet, the function and regulation of Bcl3 in CTCL have not been studied. Here, we show that Bcl3 is highly expressed in CTCL Hut-78 and HH cells.

Analysis of TGFβ1 and IL-10 transcriptional regulation in CTCL cells by chromatin immunoprecipitation.

The immunosuppressive cytokines transforming growth factor β1 (TGFβ1) and interleukin-10 (IL-10) regulate a variety of biological processes including differentiation, proliferation, tissue repair, tumorigenesis, inflammation, and host defense. Aberrant expression of TGFβ1 and IL-10 has been associated with many types of autoimmune and inflammatory disorders, as well as with many types of cancer and leukemia. Patients with cutaneous T cell lymphoma (CTCL) have high levels of malignant CD4+ T cells expressing IL-10 and TGFβ1 that suppress the immune system and diminish the antitumor responses.

Chromatin immunoprecipitation analysis of bortezomib-mediated inhibition of NFκB recruitment to IL-1β and TNFα gene promoters in human macrophages.

Interleukin-1β (IL-1) and tumor necrosis factor-α (TNF) are important pro-inflammatory cytokines involved in the mediation of the immune response, inflammation, tissue repair, and tumor progression. Regulation of IL-1 and TNF expression is mediated at the level of transcription by the transcription factor NFκB. Inhibition of NFκB activity by the proteasome inhibitor bortezomib (BZ) has been used as a frontline therapy in multiple myeloma and other hematological malignancies.

Proteasome inhibition increases recruitment of IκB kinase β (IKKβ), S536P-p65, and transcription factor EGR1 to interleukin-8 (IL-8) promoter, resulting in increased IL-8 production in ovarian cancer cells.

Proinflammatory and pro-angiogenic chemokine interleukin-8 (IL-8, CXCL8) contributes to ovarian cancer progression through its induction of tumor cell proliferation, survival, angiogenesis, and metastasis. Proteasome inhibition by bortezomib, which has been used as a frontline therapy in multiple myeloma, has shown only limited effectiveness in ovarian cancer and other solid tumors. However, the responsible mechanisms remain elusive.

NFκB function and regulation in cutaneous T-cell lymphoma.

The nuclear accumulation and transcriptional activity of NFκB are constitutively increased in cutaneous T-cell lymphoma (CTCL) cells, and are responsible for their increased survival and proliferation. However, in addition to the anti-apoptotic and pro-inflammatory genes, NFκB induces expression of immunosuppressive genes, such as IL-10 and TGFβ, which inhibit the immune responses and are characteristic for the advanced stages of CTCL. While the mechanisms regulating NFκB-dependent transcription of anti-apoptotic and pro-inflammatory genes have been studied extensively, very little is known about the NFκB regulation of immunosuppressive genes.

Proteasome inhibition by bortezomib increases IL-8 expression in androgen-independent prostate cancer cells: the role of IKKα.

Expression of the proinflammatory and proangiogenic chemokine IL-8, which is regulated at the transcriptional level by NF-κB, is constitutively increased in androgen-independent metastatic prostate cancer and correlates with poor prognosis. Inhibition of NF-κB-dependent transcription was used as an anticancer strategy for the development of the first clinically approved 26S proteasome inhibitor, bortezomib (BZ). Even though BZ has shown remarkable antitumor activity in hematological malignancies, it has been less effective in prostate cancer and other solid tumors; however, the mechanisms have not been fully understood.

Electrophoretic mobility shift assay analysis of NFκB transcriptional regulation by nuclear IκBα.

Transcription factor NFκB is a key regulator of genes involved in immune and inflammatory responses, as well as genes regulating cell proliferation and survival. In addition to many inflammatory disorders, NFκB is constitutively activated in a variety of human cancers and leukemia. Thus, inhibition of NFκB DNA binding activity represents an important therapeutic approach for disorders characterized by high levels of constitutive NFκB activity.

Bortezomib induces nuclear translocation of IκBα resulting in gene-specific suppression of NF-κB--dependent transcription and induction of apoptosis in CTCL.

Cutaneous T-cell lymphoma (CTCL) is characterized by constitutive activation of nuclear factor κB (NF-κB), which plays a crucial role in the survival of CTCL cells and their resistance to apoptosis. NF-κB activity in CTCL is inhibited by the proteasome inhibitor bortezomib; however, the mechanisms remained unknown. In this study, we investigated mechanisms by which bortezomib suppresses NF-κB activity in CTCL Hut-78 cells.

Tumor suppressor HLJ1 binds and functionally alters nucleophosmin via activating enhancer binding protein 2alpha complex formation.

HLJ1, a member of the heat shock protein 40 chaperone family, is a newly identified tumor suppressor that has been implicated in tumorigenesis and metastasis in non-small cell lung cancer. However, the mechanism of HLJ1 action is presently obscure. In this study, we report that HLJ1 specifically interacts with the nuclear protein nucleophosmin (NPM1), forming a multiprotein complex that alters the nucleolar distribution and oligomerization state of NPM1.