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Activation of PTHrP-cAMP-CREB1 signaling following p53 loss is essential for osteosarcoma initiation and maintenance.

ABSTRACT: Mutations in the P53 pathway are a hallmark of human cancer. The identification of pathways upon which p53-deficient cells depend could reveal therapeutic targets that may spare normal cells with intact p53. In contrast to P53 point mutations in other cancer, complete loss of P53 is a frequent event in osteosarcoma (OS), the most common cancer of bone. The consequences of p53 loss for osteoblastic cells and OS development are poorly understood. Here we use murine OS models to demonstrate that elevated Pthlh (Pthrp), cAMP levels and signalling via CREB1 are characteristic of both p53-deficient osteoblasts and OS. Normal osteoblasts survive depletion of both PTHrP and CREB1. In contrast, p53-deficient osteoblasts and OS depend upon continuous activation of this pathway and undergo proliferation arrest and apoptosis in the absence of PTHrP or CREB1. Our results identify the PTHrP-cAMP-CREB1 axis as an attractive pathway for therapeutic inhibition in OS.

SUBMITTER: Walia MK

PROVIDER: S-EPMC4854515 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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Activation of PTHrP-cAMP-CREB1 signaling following p53 loss is essential for osteosarcoma initiation and maintenance.

Walia Mannu K MK Ho Patricia Mw PM Taylor Scott S Ng Alvin Jm AJ Gupte Ankita A Chalk Alistair M AM Zannettino Andrew Cw AC Martin T John TJ Walkley Carl R CR

eLife 20160412

Mutations in the P53 pathway are a hallmark of human cancer. The identification of pathways upon which p53-deficient cells depend could reveal therapeutic targets that may spare normal cells with intact p53. In contrast to P53 point mutations in other cancer, complete loss of P53 is a frequent event in osteosarcoma (OS), the most common cancer of bone. The consequences of p53 loss for osteoblastic cells and OS development are poorly understood. Here we use murine OS models to demonstrate that el ...[more]

PMID: 27070462

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Project description:BackgroundWeight regain after successful weight loss interventions is common.ObjectiveTo establish the efficacy of a weight loss maintenance program compared with usual care in obese adults.Design2-group, parallel, randomized trial stratified by initial weight loss (<10 kg vs. ≥10 kg), conducted from 20 August 2012 to 18 December 2015. Outcome assessors were blinded to treatment assignment. (ClinicalTrials.gov: NCT01357551).Setting3 primary care clinics at the Veterans Affairs Medical Center in Durham and Raleigh, North Carolina.PatientsObese outpatients (body mass index ≥30 kg/m2) who lost 4 kg or more of body weight during a 16-week, group-based weight loss program.InterventionThe maintenance intervention, delivered primarily by telephone, addressed satisfaction with outcomes, relapse-prevention planning, self-monitoring, and social support. Usual care involved no contact except for study measurements.MeasurementsPrimary outcome was mean weight regain at week 56. Secondary outcomes included self-reported caloric intake, walking, and moderate physical activity.ResultsOf 504 patients in the initial program, 222 lost at least 4 kg of body weight and were randomly assigned to maintenance (n = 110) or usual care (n = 112). Retention was 85%. Most patients were middle-aged white men. Mean weight loss during initiation was 7.2 kg (SD, 3.1); mean weight at randomization was 103.6 kg (SD, 20.4). Estimated mean weight regain was statistically significantly lower in the intervention (0.75 kg) than the usual care (2.36 kg) group (estimated mean difference, 1.60 kg [95% CI, 0.07 to 3.13 kg]; P = 0.040). No statistically significant differences in secondary outcomes were seen at 56 weeks. No adverse events directly attributable to the intervention were observed.LimitationsResults may not generalize to other settings or populations. Dietary intake and physical activity were self-reported. Duration was limited to 56 weeks.ConclusionAn intervention focused on maintenance-specific strategies and delivered in a resource-conserving way modestly slowed the rate of weight regain in obese adults.Primary funding sourceVeterans Affairs Health Services Research and Development Service.

Dataset Information

Activation of PTHrP-cAMP-CREB1 signaling following p53 loss is essential for osteosarcoma initiation and maintenance.

Publications

Activation of PTHrP-cAMP-CREB1 signaling following p53 loss is essential for osteosarcoma initiation and maintenance.

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