Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) induces cancer cell senescence by interacting with telomerase RNA component.

Oxidative stress regulates telomere homeostasis and cellular aging by unclear mechanisms. Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) is a key mediator of many oxidative stress responses, involving GAPDH nuclear translocation and induction of cell death. We report here that GAPDH interacts with the telomerase RNA component (TERC), inhibits telomerase activity, and induces telomere shortening and breast cancer cell senescence. The Rossmann fold containing NAD(+) binding region on GAPDH is responsible for the interaction with TERC, whereas a lysine residue in the GAPDH catalytic domain is required for inhibiting telomerase activity and disrupting telomere maintenance. Furthermore, the GAPDH substrate glyceraldehyde-3-phosphate (G3P) and the nitric oxide donor S-nitrosoglutathione (GSNO) both negatively regulate GAPDH inhibition of telomerase activity. Thus, we demonstrate that GAPDH is regulated to target the telomerase complex, resulting in an arrest of telomere maintenance and cancer cell proliferation.

Reasons for non-attendance in youth mental health clinics: Insights from mobile messaging communications.

AIM: Non-attendance at appointments in youth mental health services is a common problem which contributes to reduced service effectiveness and unmet needs. Reasons cited by young people for non-attendance are poorly understood. Information derived from short-message-service (SMS) conversations about appointments between patients and clinicians can uncover new insights about the circumstances leading to 'did not attend' events. METHODS: Text messages between young people and clinicians were examined in a retrospective audit of medical records in two youth mental health services in Perth, Australia. Frequently non-attending young people aged 16-24 (n = 40) engaged in 302 SMS message chains about appointments. Mixed methods included quantitative data and qualitative thematic analysis of textual data. RESULTS: Medical reasons (32/190, 16.8%) and forgetfulness (20/190, 10.5%) were the most frequent reasons for non-attendance. Major issues included non-avoidable events while others were potentially preventable and could be addressed by the service. CONCLUSIONS: The analysis of mobile communications in clinical practice can be used for service evaluation and to reveal barriers that impede attendance to ongoing care.

GAPDH: a common enzyme with uncommon functions.

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) has long been recognized as an important enzyme for energy metabolism and the production of ATP and pyruvate through anaerobic glycolysis in the cytoplasm. Recent studies have shown that GAPDH has multiple functions independent of its role in energy metabolism. Although increased GAPDH gene expression and enzymatic function is associated with cell proliferation and tumourigenesis, conditions such as oxidative stress impair GAPDH catalytic activity and lead to cellular aging and apoptosis. The mechanism(s) underlying the effects of GAPDH on cellular proliferation remains unclear, yet much evidence has been accrued that demonstrates a variety of interacting partners for GAPDH, including proteins, various RNA species and telomeric DNA. The present mini review summarizes recent findings relating to the extraglycolytic functions of GAPDH and highlights the significant role this enzyme plays in regulating both cell survival and apoptotic death.

Chromosomal and telomeric reprogramming following ES-somatic cell fusion.

Chromosomal and telomeric reprogramming was assessed in intraspecies hybrids obtained by fusion of embryonic stem (ES) cells and mouse embryonic fibroblasts. Evaluation of the ploidy of ES-somatic hybrids revealed that 21 of 59 clones had a tetraploid DNA profile while the remaining clones showed deviations from the expected profile of fusion between two diploid cells. Microsatellite polymerase chain reaction analysis of four of these clones demonstrated no random loss of somatic chromosome pairs in the ES-somatic cell hybrids. Pluripotential of ES-somatic hybrids was assessed by gene expression analysis, antibody staining for Oct4 and SSEA-1 and teratoma formation containing derivatives of the three germ layers. Reprogramming of telomeric maintenance was observed with ES-somatic hybrids showing high telomerase activity and increased telomere lengths. However, we detected no significant increase in the expression of the three critical telomerase subunits: telomerase reverse transcriptase (TERT), telomerase RNA component (TERC), and dyskerin. This indicates that activation of telomerase and telomere maintenance is not reliant on changes in gene expression of TERT, TERC, and dyskerin following ES-somatic cell fusion or sister chromatid recombination and may arise through elimination of negative regulation of telomerase activity. This is the first demonstration of telomere lengthening following cell fusion and offers a new model for studying and identifying new regulators of telomere maintenance.

Homelessness youth and mental health service utilization: A long-term follow-up study.

BACKGROUND: There is currently an incomplete picture of the long-term impact of homelessness on youth with mental health issues. There are also questions regarding homelessness as a predictor of mental health re-admissions. AIMS: To examine the mental health service presentation profile of young people affected by homelessness and mental health issues. METHODS: A retrospective analysis was conducted of the medical records of homeless (n = 29) and non-homeless (n = 32) youth who attended the YouthLink specialist mental health service in 2010. We tracked their pattern of mental health service admissions at five time points during a total period of 10 years, including 2 years prior to, and up to 8 years following the YouthLink presentation. A regression analysis was used to examine factors hypothesized to contribute to mental health re-admissions. RESULTS: Homeless youth had significantly more frequent presentations to inpatient and outpatient mental health services, and emergency departments for mental health reasons. They were 11 times more likely to be re-admitted to a mental health inpatient ward than non-homeless youth. Prior hospital admission was an independent predictor, increasing by a factor of 2.2 for every inpatient admission. CONCLUSION: The impact of homelessness on mental health issues is enduring, and is a long-term predictor of hospital re-admission.

Bone morphogenetic protein-7 induces telomerase inhibition, telomere shortening, breast cancer cell senescence, and death via Smad3.

Human telomerase reverse transcriptase (hTERT) is central to maintain telomeres for continuous cell proliferation, but it remains unknown how extracellular cues regulate telomerase maintenance of telomeres. Here we report that the cytokine bone morphogenetic protein-7 (BMP7) induces Smad3 phosphorylation, nuclear translocation, and hTERT gene repression. BMP7 induces Smad3-dependent telomerase inhibition in a time- and concentration-dependent manner in breast cancer cells. Chronic exposure of breast cancer cells to BMP7 results in short telomeres, cell senescence, and apoptosis. Mutation of BMPRII receptor, but not TGFbetaRII, ACTRIIA, or ACTRIIB, blocked BMP7-induced repression of the hTERT gene promoter activity, leading to increased telomerase activity, lengthened telomeres, and continued cell proliferation. Expression of hTERT inhibits BMP7-induced breast cancer cell senescence and apoptosis. Thus, our data suggest that BMP7 induces breast cancer cell aging and death by a mechanism involving inhibition of telomerase activity and telomere maintenance via BMPRII receptor- and Smad3-mediated repression of the hTERT gene.

Strategies of treating cancer by cytokine regulation of chromosome end remodelling.

1. Telomeres (ends of chromosomes) undergo constant remodelling during cell development, proliferation and differentiation, as well as in neoplastic cell immortalization and transformation. How the cellular microenvironment influences telomere remodelling (lengthening or shortening) remains largely unknown. 2. Recently, studies from our laboratories and others have indicated that growth factors and cytokines have significant roles in regulating telomere remodelling and thus influence cell functions and properties. Cancer cells must maintain their already short telomeres either by the enzyme telomerase or, more rarely, through alternative lengthening of telomeres, which functions independently of cellular regulation. 3. However, application of transforming growth factor-beta family cytokines induces transcriptional inhibition of telomerase in cancer cells, leading to telomere shortening, cell senescence (ageing) and apoptosis (death) by mechanisms dependent on telomerase inhibition. Furthermore, selective gene silencing of vascular endothelial growth factor and/or the telomerase catalytic subunit (i.e. telomerase reverse transcriptase) potently inhibits the growth of cervical cancer and laryngeal squamous cancer in mice. 4. The present paper summarizes our current understanding of the negative regulation by cytokines of telomere maintenance and thus cancer cell proliferation in cultured cells and mouse models.

Activin inhibits telomerase activity in cancer.

Activin is a pleiotropic cytokine with broad tissue distributions. Recent studies demonstrate that activin-A inhibits cancer cell proliferation with unknown mechanisms. In this report, we demonstrate that recombinant activin-A induces telomerase inhibition in cancer cells. In breast and cervical cancer cells, activin-A resulted in telomerase activity in a concentration-dependent manner. Significant inhibition was observed at 10 ng/ml of activin-A, with a near complete inhibition at 80 ng/ml. Consistently, activin-A induced repression of the telomerase reverse transcriptase (hTERT) gene, with the hTERT gene to be suppressed by 60-80% within 24h. In addition, activin-A induced a concomitant increase in Smad3 signaling and decrease of the hTERT gene promoter activity in a concentration-dependent fashion. These data suggest that activin-A triggered telomerase inhibition by down-regulating hTERT gene expression is involved in activin-A-induced inhibition of cancer cell proliferation.

Intensive community treatment and support "Youth Wraparound" service in Western Australia: A case and feasibility study.

BACKGROUND: Multiple services are often needed to address the needs of young people with complex emotional or behavioural needs. The Youth Wraparound model of service aims to provide all health and supportive services from one coordinating agency. While this has been researched overseas, there are currently few examples of this described in the Australian psychiatric context. AIM: To document the implementation and evaluation of a Youth Wraparound service which was provided to a young person with exceptionally complex and challenging needs for 6 months. A single-case study design is presented with an evaluation of the clinical outcome and economic costs. METHODS: We present a description of the service context, principles of the model of care, implementation process, and an evaluation of service utilization data from health and child protection services and mental health records. A single-case longitudinal design compared service utilization data obtained up to 3 years prior to treatment with data collected one and a half years since treatment commenced. RESULTS: There were significant reductions in the number of admissions to emergency departments, mental health wards and secure units, and improvements in mental health and well-being. Yearly average time in institutional settings reduced from 69% to 7%. Cost savings in health utilization were estimated at $2 326 790. CONCLUSIONS: The Youth Wraparound model has the potential to offer improved clinical outcomes, significant cost savings over time, improved coordination between care providers, and an alternative to detention or incarceration.

Providing culturally informed mental health services to Aboriginal youth: The YouthLink model in Western Australia.

AIM: Aboriginal young people are more likely to experience mental health issues and to access mental health services than other young Australians, yet there are few culturally informed mental health programs and services available. This study describes and documents the effectiveness of the culturally sensitive model within YouthLink, a state-wide mental health service program in Western Australia for young people aged 13 to 24 years of age. METHODS: A mixed-method design including a descriptive approach reporting on the YouthLink framework and an empirical research design where 40 Aboriginal clients completed client feedback monitoring measures between 2014 and 2016. RESULTS: The YouthLink culturally informed conceptual framework adheres to best practice principles relevant to work with Indigenous people, family and communities. Aboriginal young people indicated improvement across the treatment period as shown by within-group differences between the first and last session scores on feedback measures. Therapeutic alliance (together with lower baseline acuity and female gender) also contributed significantly to positive treatment outcomes. CONCLUSIONS: Through a strong role of Aboriginal practitioners, relationships with Aboriginal communities, and greater service flexibility that embraces cultural meaning and knowledge, YouthLink has sought to enhance its response to the needs of Aboriginal youth.

TGF-beta receptor mediated telomerase inhibition, telomere shortening and breast cancer cell senescence.

Human telomerase reverse transcriptase (hTERT) plays a central role in telomere lengthening for continuous cell proliferation, but it remains unclear how extracellular cues regulate telomerase lengthening of telomeres. Here we report that the cytokine bone morphogenetic protein-7 (BMP7) induces the hTERT gene repression in a BMPRII receptor- and Smad3-dependent manner in human breast cancer cells. Chonic exposure of human breast cancer cells to BMP7 results in short telomeres, cell senescence and apoptosis. Mutation of the BMPRII receptor, but not TGFbRII, ACTRIIA or ACTRIIB receptor, inhibits BMP7-induced repression of the hTERT gene promoter activity, leading to increased telomerase activity, lengthened telomeres and continued cell proliferation. Expression of hTERT prevents BMP7-induced breast cancer cell senescence and apoptosis. Thus, our data suggest that BMP7 induces breast cancer cell aging by a mechanism involving BMPRII receptor- and Smad3-mediated repression of the hTERT gene.

Molecular regulation of telomerase activity in aging.

The process of aging is mitigated by the maintenance and repair of chromosome ends (telomeres), resulting in extended lifespan. This review examines the molecular mechanisms underlying the actions and regulation of the enzyme telomerase reverse transcriptase (TERT), which functions as the primary mechanism of telomere maintenance and regulates cellular life expectancy. Underpinning increased cell proliferation, telomerase is also a key factor in facilitating cancer cell immortalization. The review focuses on aspects of hormonal regulations of telomerase, and the intracellular pathways that converge to regulate telomerase activity with an emphasis on molecular interactions at protein and gene levels. In addition, the basic structure and function of two key telomerase enzyme components-the catalytic subunit TERT and the template RNA (TERC) are discussed briefly.

Telomere protein complexes and interactions with telomerase in telomere maintenance.

Telomeres are the termini of linear chromosomes. They are composed of DNA and DNA-binding proteins critical for maintaining chromosome integrity and cellular function. Telomere binding proteins regulate the structure and function of telomeres through the formation of different complexes with telomeric DNA. Double- and single-stranded telomeric DNA binding protein complexes have shared and unique functions that regulate telomere homeostasis. Recent studies have shown that telomerase interacts with several telomere-binding protein complexes including shelterin, CST, DNA-dependent protein kinase (DNA-PK) and MRN. The present review describes the recognised telomere-binding protein complexes, sub-complex exchanges and inter-complex molecular interactions. It also discusses the evidence suggesting that telomerase reverse transcriptase (TERT) switches between different complexes. Studies of the telomere protein inter-complex interactions and the switching of components between complexes provide insight into their fundamental roles of programming telomere length and configuration, and thus cell proliferative potential.

Comparison of reprogramming ability of mouse ES and iPS cells measured by somatic cell fusion.

The ectopic expression of the key transcription factors Oct4, Sox2, c-Myc, and Klf-4 have been shown to reprogram somatic cells to a pluripotent state. In turn these induced pluripotent stem (iPS) cells, like embryonic stem (ES) cells, have been shown to be able to reprogram somatic cells by cell fusion. In this study we compare the differences and similarities between ES and iPS cells measured by somatic cell fusion to somatic cells harboring an Oct4-GFP transgene. We found that iPS cells were just as potent as ES cells at reprogramming the somatic genome as measured by Oct4-GFP reactivation. The resulting ES-somatic and iPS-somatic cell hybrids were characterized for expression of key pluripotency genes, immunostaining for Oct4, SSEA-1, and the ability to differentiate into cell types representative of the three germ layers. In addition to restoring pluripotency to the somatic genome following cell fusion, the telomere maintenance mechanisms of both the ES and iPS cells were found to be dominant in the resulting ES-somatic and iPS-somatic cell hybrids, resulting in the lengthening of the somatic telomeres following cellular reprogramming. Therefore this study supports the view that iPS cells can be virtually indistinguishable from ES cells, even with regard to their reprogramming ability.

Regulation of telomerase activity by apparently opposing elements.

Telomeres, the ends of chromosomes, undergo frequent remodeling events that are important in cell development, proliferation and differentiation, and neoplastic immortalization. It is not known how the cellular environment influences telomere remodeling, stability, and lengthening or shortening. Telomerase is a ribonucleoprotein complex that maintains and lengthens telomeres in the majority of cancers. Recent studies indicate that a number of factors, including hormones, cytokines, ligands of nuclear receptor, vitamins and herbal extracts have significantly influence telomerase activity and, in some instances, the remodeling of telomeres. This review summarizes the advances in understanding of the positive and negative regulation by extracellular factors of telomerase activity in cancer, stem cells and other systems in mammals.

Bone morphogenetic protein-7 inhibits telomerase activity, telomere maintenance, and cervical tumor growth.

Telomere maintenance is critical in tumor cell immortalization. Here, we report that the cytokine bone morphogenetic protein-7 (BMP7) inhibits telomerase activity that is required for telomere maintenance in cervical cancer cells. Application of human recombinant BMP7 triggers a repression of the human telomerase reverse transcriptase (hTERT) gene, shortening of telomeres, and hTERT repression-dependent cervical cancer cell death. Continuous treatment of mouse xenograft tumors with BMP7, or silencing the hTERT gene, results in sustained inhibition of telomerase activity, shortening of telomeres, and tumor growth arrest. Overexpression of hTERT lengthens telomeres and blocks BMP7-induced tumor growth arrest. Thus, BMP7 negatively regulates telomere maintenance, inducing cervical tumor growth arrest by a mechanism of inducing hTERT gene repression.