Corrected and Republished from: The COP9 Signalosome Interacts with and Regulates Interferon Regulatory Factor 5 Protein Stability.

The transcription factor interferon regulatory factor 5 (IRF5) exerts crucial functions in the regulation of host immunity against extracellular pathogens, DNA damage-induced apoptosis, death receptor signaling, and macrophage polarization. Tight regulation of IRF5 is thus warranted for an efficient response to extracellular stressors and for limiting autoimmune and inflammatory responses. Here we report that the COP9 signalosome (CSN), a general modulator of diverse cellular and developmental processes, associates constitutively with IRF5 and promotes its protein stability.

Loss of the xeroderma pigmentosum group B protein binding site impairs p210 BCR/ABL1 leukemogenic activity.

Previous studies have demonstrated that p210 BCR/ABL1 interacts directly with the xeroderma pigmentosum group B (XPB) protein, and that XPB is phosphorylated on tyrosine in cells that express p210 BCR/ABL1. In the current study, we have constructed a p210 BCR/ABL1 mutant that can no longer bind to XPB. The mutant has normal kinase activity and interacts with GRB2, but can no longer phosphorylate XPB.

Deletion of Irf5 protects hematopoietic stem cells from DNA damage-induced apoptosis and suppresses γ-irradiation-induced thymic lymphomagenesis.

Repeated low-dose γ-irradiation (IR) induces thymic lymphoma in mice because of oncogenic mutations propagating from a primitive hematopoietic stem/progenitor cell (HSC) in the bone marrow. It is well known that IR-induced thymic lymphomagenesis is markedly enhanced by p53 deficiency, yet data also indicate that p53-dependent apoptosis can actively drive tumor formation in this model. The latter was recently expounded on by findings from Puma-deficient mice, indicating that loss of this proapoptotic p53 target gene results in protection from IR-induced lymphomagenesis rather than enhanced susceptibility to.

Establishing a minority-based community clinical oncology program: the University of Medicine and Dentistry of New Jersey, New Jersey Medical School-university Hospital Cancer Center experience.

The Minority-Based Community Clinical Oncology Program (MB-CCOP) at University of Medicine and Dentistry of New Jersey, New Jersey Medical School-University Hospital Cancer Center was established to serve an unmet need in a medically, educationally, and socioeconomically underserved community of primarily African American and Latino patients in Newark and Essex County, New Jersey. The MB-CCOP was built on an existing infrastructure of multidisciplinary teams of cancer specialists who collaborated in patient care and an existing clinical research program, which included multilingual staff and a breast cancer navigator. This article highlights some of the unique opportunities and challenges involved in the startup of an MB-CCOP specifically relevant to an academic setting.

RNA-Seq for enrichment and analysis of IRF5 transcript expression in SLE.

Polymorphisms in the interferon regulatory factor 5 (IRF5) gene have been consistently replicated and shown to confer risk for or protection from the development of systemic lupus erythematosus (SLE). IRF5 expression is significantly upregulated in SLE patients and upregulation associates with IRF5-SLE risk haplotypes. IRF5 alternative splicing has also been shown to be elevated in SLE patients.

Cooperative activation of tissue-specific genes by pRB and E2F1.

The retinoblastoma tumor suppressor protein pRB is conventionally regarded as an inhibitor of the E2F family of transcription factors. Conversely, pRB is also recognized as an activator of tissue-specific gene expression along various lineages including osteoblastogenesis. During osteoblast differentiation, pRB directly targets Alpl and Bglap, which encode the major markers of osteogenesis alkaline phosphatase and osteocalcin.

Contributions of the RhoGEF activity of p210 BCR/ABL to disease progression.

We have previously identified a tyrosine kinase-independent, guanine nucleotide exchange factor (GEF) activity, which is contained within the region of p210 no expansion BCR/ABL that distinguishes it from p190 BCR/ABL. In the current study, we have compared the transforming activity of p190 BCR/ABL, p210 BCR/ABL and a mutant that lacks GEF activity (p210 BCR/ABL(S509A)). In cell-based, ex vivo, and murine bone marrow transplantation (BMT) assays the transforming activity of p210 BCR/ABL(S509A) mimics p190 BCR/ABL, and is distinct from p210 BCR/ABL.

Oncogene-induced telomere dysfunction enforces cellular senescence in human cancer precursor lesions.

In normal human somatic cells, telomere dysfunction causes cellular senescence, a stable proliferative arrest with tumour suppressing properties. Whether telomere dysfunction-induced senescence (TDIS) suppresses cancer growth in humans, however, is unknown. Here, we demonstrate that multiple and distinct human cancer precursor lesions, but not corresponding malignant cancers, are comprised of cells that display hallmarks of TDIS.

Concomitant inactivation of Rb and E2f8 in hematopoietic stem cells synergizes to induce severe anemia.

The retinoblastoma (Rb) tumor suppressor plays important roles in regulating hematopoiesis, particularly erythropoiesis. In an effort to understand whether Rb function can be mediated by E2F transcription factors in a BM-derived hematopoietic system in mice, we uncovered a functional synergy between Rb and E2F8 to promote erythropoiesis and to prevent anemia. Specifically, whereas Mx1-Cre-mediated inactivation of Rb or E2f8 in hematopoietic stem cells only led to mild erythropoietic defects, concomitant inactivation of both genes resulted in marked ineffective erythropoiesis and mild hemolysis, leading to severe anemia despite the presence of enhanced extramedullary erythropoiesis.

Essential role of ARID2 protein-containing SWI/SNF complex in tissue-specific gene expression.

Unfolding of the gene expression program that converts precursor cells to their terminally differentiated counterparts is critically dependent on the nucleosome-remodeling activity of the mammalian SWI/SNF complex. The complex can be powered by either of two alternative ATPases, BRM or BRG1. BRG1 is critical for development and the activation of tissue specific genes and is found in two major stable configurations.

Interferon regulatory factor 5 activation in monocytes of systemic lupus erythematosus patients is triggered by circulating autoantigens independent of type I interferons.

Objective: Genetic variants of interferon regulatory factor 5 (IRF-5) are associated with susceptibility to systemic lupus erythematosus (SLE). IRF-5 regulates the expression of proinflammatory cytokines and type I interferons (IFNs) believed to be involved in the pathogenesis of SLE. The aim of this study was to determine the activation status of IRF-5 by assessing its nuclear localization in the immune cells of SLE patients and healthy donors, and to identify SLE-associated triggers of IRF-5 activation.

Tissue-specific gene targeting by the multiprotein mammalian DREAM complex.

The mammalian DP, RB-like, E2F, and MuvB-like proteins (DREAM) complex, whose key components include p130 and E2F4, plays a fundamental role in repression of cell cycle-specific genes during growth arrest. Mammalian DREAM is well conserved with Drosophila and Caenorhabditis elegans complexes that repress pivotal developmental genes, but the mammalian complex has been thought to exist only in quiescent cells and not to be linked with development. However, new findings here identify tissue-specific promoters repressed by DREAM in proliferating precursors, revealing a new connection between control of growth arrest and terminal differentiation.

Transcriptional activation by pRB and its coordination with SWI/SNF recruitment.

A central question in cancer biology is why most tumor susceptibility genes are linked with only limited types of cancer. Human germ-line mutation of the retinoblastoma susceptibility gene Rb1 is closely linked with just retinoblastoma and osteosarcoma, although the gene is universally expressed. Functional analysis of pRB and its close relatives, p107 and p130, has largely focused on their roles in repression of proliferation across all tissue types, but genetic evidence indicates an active requirement for pRB in osteoblast differentiation that correlates more directly with osteosarcoma susceptibility.

A pilot phase II trial of all-trans retinoic acid (Vesanoid) and paclitaxel (Taxol) in patients with recurrent or metastatic breast cancer.

Purpose: We investigated a combination therapy with weekly paclitaxel and all trans-retinoic acid (ATRA) for tolerability, response to treatment, time to progression and survival in previously treated patients with metastatic or recurrent breast cancer. Our rationale was based on preclinical studies demonstrating potentiation of the cytotoxic effects of taxanes and induction of differentiation by ATRA.

Patients And Methods: Seventeen patients with previously treated metastatic or recurrent breast cancer were enrolled to a regimen of all-trans retinoic acid (Vesanoid, tretinoin, Hoffman-La Roche, Inc.

PHF10 is required for cell proliferation in normal and SV40-immortalized human fibroblast cells.

Normal human diploid fibroblasts have limited life span in culture and undergo replicative senescence after 50-60 population doublings. On the contrary, cancer cells typically divide indefinitely and are immortal. Expression of SV40 large T and small t antigens in human fibroblasts transiently extends their life span by 20-30 population doublings and facilitates immortalization.

The rho-specific guanine nucleotide exchange factor Dbs regulates breast cancer cell migration.

Dbs is a Rho-specific guanine nucleotide exchange factor (RhoGEF) that regulates neurotrophin-3-induced cell migration in Schwann cells. Here we report that Dbs regulates cell motility in tumor-derived, human breast epithelial cells through activation of Cdc42 and Rac1. Cdc42 and Rac1 are activated in T47D cells that stably express onco- or proto-Dbs, and activation is dependent upon growth of the cells on collagen I.

Dual FGF-2 and intergrin alpha5beta1 signaling mediate GRAF-induced RhoA inactivation in a model of breast cancer dormancy.

Interactions with the bone marrow stroma regulate dormancy and survival of breast cancer micrometastases. In an in vitro model of dormancy in the bone marrow, we previously demonstrated that estrogen-dependent breast cancer cells are partially re-differentiated by FGF-2, re-express integrin alpha5beta1 lost with malignant transformation and acquire an activated PI3K/Akt pathway. Ligation of integrin alpha5beta1 by fibronectin and activation of the PI3K pathway both contribute to survival of these dormant cells.

Antagonistic roles for BRM and BRG1 SWI/SNF complexes in differentiation.

The mammalian SWI/SNF chromatin-remodeling complex is essential for the multiple changes in gene expression that occur during differentiation. However, the basis within the complex for specificity in effecting positive versus negative changes in gene expression has only begun to be elucidated. The catalytic core of the complex can be either of two closely related ATPases, BRM or BRG1, with the potential that the choice of alternative subunits is a key determinant of specificity.

Regulation of apoptosis by type III interferons.

Objective: Two types of interferons (IFNs), type I (IFN-alpha/beta) and type III (IFN-lambdas), utilize distinct receptor complexes to induce similar signalling and biological activities, including recently demonstrated for IFN-lambdas antitumour activity. However, ability of type III IFNs to regulate cell population growth remains largely uncharacterized.

Materials And Methods: Intact and modified human colorectal adenocarcinoma HT29 cells were used to study regulation of apoptosis by IFN-lambdas.

Influence of prescription benefits on reported pain in cancer patients.

Objective: To identify associations between prescription coverage and cancer pain and its sequelae in indigent patients.

Design And Setting: A retrospective chart review at UMDNJ-University Hospital.

Patients And Outcome Measures: Charts from 20 patients with Medicaid and 20 patients categorized as Self-pay/Charity Care were analyzed for the influence of insurance coverage on reported pain at the time of a hospital discharge and at three subsequent clinic visits.

Image-based study of interferongenic interactions between plasmacytoid dendritic cells and HSV-infected monocyte-derived dendritic cells.

Plasmacytoid dendritic cells (pDC) are well-known for their ability to produce large quantities of interferon-alpha (IFN-alpha) in response to viruses. In addition, pDC produce IFN-alpha in response to HSV-infected cells. We demonstrate that both tonsil and PBMC contain pDC that respond to stimulation with HSV either in suspension or in tonsil tissue-fragment culture.

The RhoGEF domain of p210 Bcr-Abl activates RhoA and is required for transformation.

The BCR-ABL oncogene encodes an in-frame fusion protein containing N-terminal sequences derived from Bcr and C-terminal sequences derived from Abl. Bcr contains a centrally located Rho-specific guanine nucleotide exchange factor (RhoGEF) domain that is retained within p210 Bcr-Abl. Although this domain is subject to autoinhibition in the context of Bcr, here we show that it is constitutively activated in p210 Bcr-Abl.