Growth hormone (GH) suppresses DNA damage repair in human prostate epithelial cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE298387 | GEO | 2026/05/31
REPOSITORIES: GEO
Similar Datasets
Project description:Oxidative DNA damage in neurons activates a DNA damage response (DDR) to promote repair. Under a chronic oxidative environment these processes may be altered and promote accumulation of unrepaired DNA damage and continued activation of a DDR, leading to apoptosis or senescence activation. Accumulation of oxidative DNA damage are features of brain ageing and neurodegeneration but the effects of persistent DNA damage in neurons are not well characterised. We developed a model of persistent oxidative DNA damage in human neurons in vitro (LUHMES) by exposing them to a sub-lethal concentration of hydrogen peroxide (H2O2) following a "single stress" and “double stress” protocols. We characterised the neuronal transcriptome under these circumstances using microarray analysis.
2023-11-04 | GSE160841 | GEO
Project description:Comprehensive Model Description
Overview
This model simulates the cellular response to DNA damage under conditions of ATM/ATR deficiency—such as in ataxia telangiectasia—and predicts the potential benefits of drug repositioning with Omaveloxolone and spermidine. It integrates several interconnected modules: DNA damage production and repair, ATM/ATR–p53 signaling, NRF2/KEAP1 regulation, spermidine-induced autophagy (with additional positive modulation of ATR signaling), and downstream p53 effectors involved in cell fate decisions.
1. DNA Damage Production and Repair Module
Basal DNA Damage Production:
DNA damage is continuously generated at a constant rate, representing both endogenous processes and low-level environmental stress. This reaction acts as a source term for the DNA_damage species.
Repair Pathways:
Several mechanisms work to reduce DNA damage:
ATM-Mediated Repair: Active ATM facilitates the direct repair of DNA damage.
ATR-Mediated Repair: Active ATR, in cooperation with CHK1, repairs DNA damage.
NRF2-Mediated Repair: Active NRF2 triggers antioxidant responses that reduce DNA damage.
Autophagy-Mediated Repair: The autophagy pathway, induced by spermidine, repairs DNA damage in a saturable manner (modeled using Michaelis–Menten kinetics). This ensures that even a significant pulse of damage is only partially repaired, leaving a nonzero steady-state level.
2. ATM/ATR–p53 Signaling Module
ATM and ATR Activation:
DNA damage, along with a positive input from TOPBP1, converts inactive ATM and ATR to their active forms. Under ATM/ATR-deficient conditions (as in ataxia telangiectasia), the activation is severely reduced, resulting in higher levels of unrepaired DNA damage.
p53 Activation:
Both ATM_active and ATR_active phosphorylate and activate p53. Active p53 then acts as a central integrator of the DNA damage signal.
Regulatory Proteins:
HDAC4:
HDAC4 cycles between inactive and active states. Its active form can attenuate p53 activity.
TOPBP1:
TOPBP1 is activated in a DNA damage–dependent manner and helps promote ATR activation.
CK2:
CK2 is a constitutively active kinase that supports TOPBP1 activation.
3. NRF2/KEAP1 Module and Omaveloxolone
NRF2 Activation:
DNA damage stimulates the conversion of NRF2_inactive to NRF2_active. Active NRF2 enhances antioxidant defenses and promotes DNA repair.
KEAP1-Mediated Degradation:
Under normal conditions, KEAP1 targets NRF2_inactive for degradation, keeping NRF2 activity low.
Modulation by Omaveloxolone:
Omaveloxolone is modeled as a constant (boundary) species. It inhibits KEAP1’s activity, thereby reducing NRF2 degradation. This shifts the balance in favor of increased NRF2_active, which boosts the cell’s antioxidant and repair responses.
4. Spermidine-Induced Autophagy and Positive Modulation of ATR Signaling
Spermidine is modeled as a constant species and has two major effects:
Induction of Autophagy:
Spermidine promotes the conversion of Autophagy_inactive to Autophagy_active. The active autophagy machinery repairs DNA damage using a saturable (Michaelis–Menten) mechanism. This pathway helps clear DNA damage but is limited by its maximum capacity.
Enhancement of ATR Signaling:
Spermidine also positively modulates ATR signaling by enhancing the CK2-mediated activation of TOPBP1. In the model, the effective rate of TOPBP1 activation is increased proportionally to the concentration of spermidine. This is represented by a modulation factor, where the effective rate constant for TOPBP1 activation is multiplied by a term that increases with spermidine concentration. The boosted TOPBP1_active level in turn enhances ATR activation, partially compensating for the loss of ATM/ATR function.
5. Downstream p53 Targets: Cell Fate Decisions
Activated p53 regulates cell fate by inducing the production of several downstream effectors:
p21:
p21 is produced in response to p53 activation and is associated with cell cycle arrest and senescence. Its production is balanced by a degradation reaction.
BAX and PUMA:
Both BAX and PUMA are pro-apoptotic proteins. They are produced in proportion to p53_active and are subsequently degraded. Their relative levels help determine whether the cell will undergo apoptosis.
6. Reaction Kinetics (Qualitative Overview)
Mass-Action and Michaelis–Menten Kinetics:
Most reactions in the model are governed by mass-action kinetics. For example, activation and deactivation reactions (such as ATM activation by DNA damage or p53 activation by ATM/ATR) follow simple proportional relationships.
Saturable Repair Processes:
The autophagy-mediated DNA repair reaction uses Michaelis–Menten kinetics to reflect a saturation effect; when DNA damage is high, the repair rate approaches a maximum value, ensuring that not all damage is cleared immediately.
Modulatory Effects:
Spermidine increases the effective rate of TOPBP1 activation (and hence ATR activation) via a modulation term that is proportional to its concentration. Omaveloxolone reduces the degradation rate of NRF2 by inhibiting KEAP1.
Biological Implications and Model Utility
ATM/ATR Deficiency:
In ataxia telangiectasia, ATM/ATR functions are diminished, leading to increased DNA damage. The model simulates this scenario and examines how alternative pathways (NRF2-mediated repair, autophagy, and enhanced ATR signaling via spermidine) help mitigate the damage.
Drug Repositioning Predictions:
The model can be used to predict the outcomes of repositioning drugs:
Omaveloxolone is expected to stabilize NRF2, enhancing antioxidant defenses and reducing DNA damage.
Spermidine acts dually by promoting autophagy (with a saturable repair capacity) and by boosting ATR signaling via TOPBP1 activation.
Cell Fate Outcomes:
The downstream p53 targets (p21, BAX, and PUMA) serve as markers for cell cycle arrest/senescence and apoptosis. By simulating the dynamics of these proteins, the model can predict whether a cell is likely to survive, arrest its cycle, or undergo apoptosis based on the integrated response to DNA damage and drug interventions.
Conclusion
This detailed and comprehensive model integrates multiple layers of the cellular response to DNA damage in ATM/ATR-deficient conditions. It includes upstream damage sensing, multiple repair pathways (including direct kinase-mediated repair, antioxidant responses via NRF2, and autophagy-mediated repair), and downstream effectors that determine cell fate. Omaveloxolone and spermidine are modeled to specifically modulate the NRF2/KEAP1 pathway and ATR signaling (via TOPBP1 activation), respectively. This framework provides a robust platform for exploring drug repositioning strategies and predicting cellular outcomes in diseases such as ataxia telangiectasia.
2025-11-25 | MODEL2503190002 | BioModels
Project description:Adipose tissue is a major target of GH action. GH stimulates lipolysis and reduces fat mass. The molecular mechanism underlying cellular and metabolic effects of GH in adipose tissue is not well understood. The aim of this study is to identify GH-responsive genes that regulate lipid metabolism in adipose tissue. Eight men with GH deficiency underwent measurement of plasma free fatty acid (FFA), whole body lipid oxidation and fat biopsies before and after one month of GH treatment (0.5mg/day). Gene expression profiling was performed using Agilent 44K G4112F arrays utilising a two-colour design. Differentially expressed genes were identified using an empirical Bayes, moderate t-test, with a false discovery rate of < 5%. Genes involved in GH receptor signalling, lipolysis, triglyceride biosynthesis, adipocyte differentiation and function were analysed. Target genes were validated by quantitative RT-PCR. GH increased circulating IGF-I and FFA and stimulated fat oxidation. A total of 246 genes were differentially expressed, of which 135 were up-regulated and 111 down-regulated. GH enhanced adipose tissue expression of IGF-I and SOCS3. It did not change expression of key enzymes governing lipolysis, but differentially regulated genes promoting diacylglycerol syntheses. GH repressed hydroxysteroid (11-beta) dehydrogenase 1, which activates local cortisol production, and genes encoding components of extracellular matrix that regulate inflammation. GH induced concordant change in circulating IGF-I and expression in adipose tissue. GH stimulation of lipolysis is mediated at a translational and/or post-translational level. GH suppressed genes encoding local factors regulating adipocyte differentiation, function and inflammation.
2010-12-31 | E-MTAB-276 | biostudies-arrayexpress
Project description:Xeroderma Pigmentosum C (XPC) is a DNA damage recognition protein central to the global genome nucleotide excision repair (GG-NER) pathway, where it acts as a primary sensor of UV-induced DNA lesions. Loss-of-function mutations in the XPC gene lead to a photosensitive phenotype, with marked accumulation of unrepaired DNA damage and a dramatically elevated risk (10,000-fold) of skin cancer. This work aims at understanding the molecular signaling mechanisms associated with XP-C using genetically engineered human XPC knockout (KO) keratinocytes, the predominant cell type affected by UV radiation. We performed a mass spectrometry (MS)-based quantitative proteomic analysis, comparing XPC-wild-type and XPC-KO keratinocytes exposed or not to UVB for 24 hours.
2026-02-23 | PXD069309 | Pride
Project description:Unrepaired DNA damage contributes to brain aging and neurodegenerative diseases. However, the factors stimulating DNA repair activity to stave off age-associated functional decline remain obscure. Here, we show that histone deacetylase 1 (HDAC1) modulates DNA repair in the aging brain via targeting OGG1 of the base excision repair pathway. Mice deficient in HDAC1 display age-associated accumulation of DNA damage in the brain and cognitive impairment. HDAC1 interacts with and positively stimulates OGG1, a DNA glycosylase that primarily acts on 8-oxoguanine (8-oxoG), a type of oxidative DNA damage associated with transcriptional repression. Loss of HDAC1 leads to impaired OGG1 activity, 8-oxoG accumulation at the promoters of a subset of genes critical for brain function, and transcriptional repression. Moreover, we observe elevated 8-oxoG lesions along with reduced HDAC1 activity and downregulation of a similar set genes in the 5XFAD mouse model of Alzheimer’s disease (AD). Notably, pharmacological activation of HDAC1 confers protection against the deleterious effects of 8-oxoG lesions in the brains of aged wild-type and 5XFAD mice. Our work uncovers an important role for HDAC1 in the repair of 8-oxoG lesions and highlights HDAC1 activation as a novel therapeutic strategy to counter functional decline during brain aging and neurodegeneration.
2020-03-30 | GSE115437 | GEO
Project description:DNA damage comprises a causal factor for aging and aging-associated diseases. Defects in genome maintenance pathways give rise to a variety of human congenital syndromes that are characterized by growth retardation, cancer susceptibility, and accelerated aging. The specific consequences of unrepaired DNA damage in human diseases are particularly apparent in syndromes caused by distinct nucleotide excision repair (NER) defects, however, with yet poorly understood genotype-phenotype correlations and highly complex disease phenotypes. We have established that the equivalent mutations in the simple metazoan Caenorhabditis elegans reflect the distinct outcomes of DNA repair defects and allow investigating the consequences of persistent DNA damage during animal development and aging. Here, we employed proteome, lipidome, and phosphoproteome analysis of NER-deficient animals in response to UV treatment in order to gain comprehensive insights into the full range of physiological adaptations to the presence of unrepaired DNA damage. We derive metabolic changes indicative of a tissue maintenance program and implicate an autophagy-mediated protoestatic response. We assign central roles for the IIS regulator DAF-2 and the EGF-signalling pathway in orchestrating this adaptive response to DNA damage. Our results provide new insights into the DNA damage responses in the organismal context.
2017-08-22 | PXD005649 | Pride
Project description:In response to DNA damage, cells arrest the cell cycle to repair damage, induce apoptosis when unrepaired, and avoid the accumulation of mutations. Our present analysis showed that oxidative stress causing DNA damage in the same condition resulted in apoptosis in induced pluripotent stem cells (iPSCs), but background levels of apoptosis in progenitor fibroblasts that just suffered cell-cycle arrest. PCA analysis of RNA-seq data and annexin V staining revealed apoptosis in iPSCs recovered within 24 hours. Characteristics as a stem cell obtained by reprogramming have shown that systems have been established that do not leave mutations in daughter cells by quickly induced apoptosis when accurate DNA repair was impossible. The surviving cells' gene expression reverts to approximately the same as that before oxidative damage in 24 hours, although the expression of error-free DNA repair-related genes has not reverted. On the other hand, the expression of error-prone polymerase POLH and REV3 revealed up-regulation. This pattern might cause the possibility of mutation in the genome after oxidative stress.
2019-10-01 | GSE138093 | GEO
Project description:Coho Salmon GH Transgenic Study Keywords: other
2005-05-01 | GSE2388 | GEO
Project description:Aging is associated with appearance of senescent cells secreting the senescence-associated secretome facilitating a milieu favoring age-related changes in microenvironment. Previously, we showed accumulation and secretion of local non-pituitary growth hormone (npGH) in senescent colon epithelial cells. Here, we elucidate mechanisms underlying npGH action in the non-tumorous colon tissue microenvironment. We demonstrate autocrine npGH action in normal human colon cells (hNCC) infected with lentivirus expressing hGH (lentiGH), as well as paracrine npGH action in hNCC cocultured with lentiGH hNCC and in intact human 3-dimensional intestinal organoids co-cultured with organoids infected with lentiGH. Enriched gene ontology and pathway analysis of intact organoids exposed to paracrine npGH identified distorted extracellular matrix (ECM) and focal adhesion pathways concurrent with altered expression of ECM and cytoskeletal proteins. Significant phosphoprotein changes associated with cytoskeleton and cell migration pathway occurred in GH-exposed hNCC. Paracrine npGH triggers these changes by activating epithelial-mesenchymal transition, as shown by suppression of E-cadherin and induction of Twist2 in cellular models, as well as in the colon of nude mice harboring GH-secreting xenografts. These changes are consistent with observed increased migration of hNCC overexpressing lentiGH, or in those co-cultured with GH-secreting hNCC or with GH-secreting normal colon fibroblasts. Furthermore, whole exome sequencing detected increased cell copy number alterations in intact organoids co-cultured with lentiGH-infected organoids, likely as a consequence of GH-mediated suppressed DNA damage repair thereby favoring cell transformation. Our results indicate that accumulated npGH in aging tissue enables a microenvironment landscape favoring age-associated pro-proliferative changes.
2025-01-08 | MSV000096807 | MassIVE
Project description:Effect of continuous GH treatment on old rat liver. Male rats, 2-year-old, were treated with vehicle or human GH (0.34 microgram/gram body weight) for 3 weeks. Keywords: response of old rat liver to growth hormone
2005-07-19 | GSE2962 | GEO