Alternative NF-κB Signaling Discriminates Induction of the Tumor Marker Fascin by the Viral Oncoproteins Tax-1 and Tax-2 of Human T-Cell Leukemia Viruses.

Transcriptional regulation of the actin-bundling protein and tumor marker Fascin is highly diverse depending on cell and tumor type. Previously, we discovered that the viral oncoprotein Tax-1 of human T-cell leukemia virus type 1 (HTLV-1) considerably enhances Fascin expression in T-cells, depending on classical NF-κB signaling. In this study, we asked if the non-oncogenic Tax-2 of the related HTLV-2 is still able to induce Fascin by using luciferase assays, immunoblot, and qPCR. We found that Tax-2 only slightly induces Fascin expression compared to Tax-1; however, both Tax-1 and Tax-2 comparably activated a 1.6 kb fragment in the human Fascin promoter including Tax-responsive elements. Furthermore, we identified a link between Tax-induced activity of the alternative NF-κB pathway and Fascin induction. While treatment with the second mitochondria-derived activator of caspases (SMAC)-mimetic AZD5582, a compound known to robustly activate alternative NF-κB signaling, did not induce Fascin, combination of AZD5582 with activation of classical NF-κB signaling by Tax-2 significantly induced Fascin expression. In conclusion, our data demonstrate that both classical and alternative NF-κB activity are necessary for strong Fascin induction by the viral Tax oncoproteins, thus, shedding new light on the regulation of Fascin in T-cells and during viral transformation.

Regulation of the tumor marker Fascin by the viral oncoprotein Tax of human T-cell leukemia virus type 1 (HTLV-1) depends on promoter activation and on a promoter-independent mechanism.

Adult T-cell leukemia/lymphoma is a highly infiltrative neoplasia of CD4(+) T-lymphocytes that occurs in about 5% of carriers infected with the deltaretrovirus human T-cell leukemia virus type 1 (HTLV-1). The viral oncoprotein Tax perturbs cellular signaling pathways leading to upregulation of host cell factors, amongst them the actin-bundling protein Fascin, an invasion marker of several types of cancer. However, transcriptional regulation of Fascin by Tax is poorly understood. In this study, we identified a triple mode of transcriptional induction of Fascin by Tax, which requires (1) NF-κB-dependent promoter activation, (2) a Tax-responsive region in the Fascin promoter, and (3) a promoter-independent mechanism sensitive to the Src family kinase inhibitor PP2. Thus, Tax regulates Fascin by a multitude of signals. Beyond, using Tax-expressing and virus-transformed lymphocytes as a model system, our study is the first to identify the invasion marker Fascin as a novel target of PP2, an inhibitor of metastasis.

The tumor marker Fascin is induced by the Epstein-Barr virus-encoded oncoprotein LMP1 via NF-κB in lymphocytes and contributes to their invasive migration.

BACKGROUND: The actin-bundling protein Fascin (FSCN1) is a tumor marker that is highly expressed in numerous types of cancer including lymphomas and is important for migration and metastasis of tumor cells. Fascin has also been detected in B lymphocytes that are freshly-infected with Epstein-Barr virus (EBV), however, both the inducers and the mechanisms of Fascin upregulation are still unclear. RESULTS: Here we show that the EBV-encoded oncoprotein latent membrane protein 1 (LMP1), a potent regulator of cellular signaling and transformation, is sufficient to induce both Fascin mRNA and protein in lymphocytes. Fascin expression is mainly regulated by LMP1 via the C-terminal activation region 2 (CTAR2). Block of canonical NF-κB signaling using a chemical inhibitor of IκB kinase ß (IKKß) or cotransfection of a dominant-negative inhibitor of IκBα (NFKBIA) reduced not only expression of p100, a classical target of the canonical NF-κB-pathway, but also LMP1-induced Fascin expression. Furthermore, chemical inhibition of IKKß reduced both Fascin mRNA and protein levels in EBV-transformed lymphoblastoid cell lines, indicating that canonical NF-κB signaling is required for LMP1-mediated regulation of Fascin both in transfected and transformed lymphocytes. Beyond that, chemical inhibition of IKKß significantly reduced invasive migration of EBV-transformed lymphoblastoid cells through extracellular matrix. Transient transfection experiments revealed that Fascin contributed to LMP1-mediated enhancement of invasive migration through extracellular matrix. While LMP1 enhanced the number of invaded cells, functional knockdown of Fascin by two different small hairpin RNAs resulted in significant reduction of invaded, non-attached cells. CONCLUSIONS: Thus, our data show that LMP1-mediated upregulation of Fascin depends on NF-κB and both NF-κB and Fascin contribute to invasive migration of LMP1-expressing lymphocytes.

The association between behavioural and emotional problems and age in adults with Down syndrome without dementia: Examining a wide spectrum of behavioural and emotional problems.

The literature on the association between behavioural and emotional problems and ageing in adults with Down syndrome (DS) without dementia is limited and has generally not reported on a wide range of behavioural and emotional problems. This research aimed to extend the field by examining the associations between age and a wide spectrum of behavioural and emotional problems in adults with DS without dementia. A preliminary analysis of the association between potential covariates and behavioural and emotional problems was also undertaken. Parents and caregivers completed a questionnaire on behavioural and emotional problems for 53 adults with DS aged between 16 and 56 years. Twenty-eight adults with DS and their caregivers were part of a longitudinal sample, which provided two time points of data approximately four years apart. Additionally, 25 participants with DS and their caregivers were from a cross sectional sample, which provided one time point of data. Random effects regression analyses were used to examine the patterns in item scores for behavioural and emotional problems associated with age. No significant associations between age and the range or severity of any behavioural and emotional items were found. This suggested a more positive pattern for ageing adults with DS than has been previously described. Given that behavioural and emotional problems were not associated with age, investigation into other factors that may be associated with the behavioural and emotional difficulties for adults with DS is discussed.

The availability of normative data for the Developmental Behaviour Checklist for Adults.

BACKGROUND: Standardised normative data for checklists of behavioural and emotional disturbance have a demonstrated usefulness for clinicians, researchers, and service providers. METHOD: The Developmental Behaviour Checklist for Adults (DBC-A) was the instrument used in a large-scale Australian study (n = 1,538) of emotional and behavioural disturbance. RESULTS: To assist the field, normative data is now available on the DBC-A for adults with ID from age 18-85 years, across three levels of intellectual disability (ID). A condensed version of DBC-A normative data is presented here. CONCLUSIONS: A large population-based study provided an opportunity for further checklist development, and the utility of the DBC-A has been enhanced by the provision of normative data.

Assessment in intellectual disability.

PURPOSE OF REVIEW: This review examines an eclectic selection of publications from the past 12 months under the broad heading of 'assessment in intellectual disability'. Being unable to cover all possible publications the authors have concentrated on the assessment of pain (in those with severe intellectual disability), psychopathology, risk assessment and offending, autism, preference and choice, and dementia. RECENT FINDINGS: Research into assessment has generally taken the form of developing new instruments, or adapting existing ones, or comparing the performance of a range of scales in a certain area. Researchers are using increasingly sophisticated psychometric analyses and refining the nature and purpose of tools for a range of clinical purposes. SUMMARY: The result of recent effort in this area is better instruments, often developed by experienced researchers who have been working in their chosen area of speciality for some years. It has been a very worthwhile period of extension and consolidation.

The assessment and treatment of behavioural problems.

BACKGROUND: While general practitioners acknowledge their responsibility for the medical management of people with intellectual disability and autism, there may be a need for more skill in the assessment and management of behavioral problems. OBJECTIVE: This article provides an overview of services for this group of patients, the role of the GP, and provides a guide to assessment and treatment of behavioural problems. DISCUSSION: While GPs have skills in medical and psychiatric assessment, the different social, cognitive and communicative context in this group of people limits their ability to apply those skills. Nonetheless, familiarity with the patient and their social environment means that GPs have an important and central role in the ongoing management of patients with an intellectual disability.

Collaboration--together we can find the way in dual diagnosis.

Service systems in health and community agencies are struggling to deliver mental health services to adults with an intellectual disability. Many professionals feel ill equipped to assess and treat mental health disorders in this population. This Australian case study describes the collaborative effort required to meet the complex health needs of a client with an intellectual disability and the needs of her family, and the role played by a specialist, Disability Health Service. The key elements of this successful interagency collaboration are outlined and include good communication, adequate resourcing, and a willingness to resolve dynamic tensions and learn from each other.