Interplay between environmentally modulated feedback loops – hypoxia and circadian rhythms – two sides of the same coin?

Depping, Reinhard; Oster, Henrik

doi:10.1111/febs.14306

Cited by 6 publications

(3 citation statements)

References 20 publications

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“…The intricate orchestration of the molecular pathways underlying cartilage development involve a delicate interplay between HIF-1α and the molecular clock machinery [ 148 , 149 ]. HIF-1α stands as a central mediator in cellular responses to hypoxia, modulating an abundance of chondrogenic genes [ 17 ].…”

Section: Future Perspectives and Research Directionsmentioning

confidence: 99%

Hypoxic Conditions Modulate Chondrogenesis through the Circadian Clock: The Role of Hypoxia-Inducible Factor-1α

Juhász,

Hajdú,

Kovács

et al. 2024

Cells

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Hypoxia-inducible factor-1 (HIF-1) is a heterodimer transcription factor composed of an alpha and a beta subunit. HIF-1α is a master regulator of cellular response to hypoxia by activating the transcription of genes that facilitate metabolic adaptation to hypoxia. Since chondrocytes in mature articular cartilage reside in a hypoxic environment, HIF-1α plays an important role in chondrogenesis and in the physiological lifecycle of articular cartilage. Accumulating evidence suggests interactions between the HIF pathways and the circadian clock. The circadian clock is an emerging regulator in both developing and mature chondrocytes. However, how circadian rhythm is established during the early steps of cartilage formation and through what signaling pathways it promotes the healthy chondrocyte phenotype is still not entirely known. This narrative review aims to deliver a concise analysis of the existing understanding of the dynamic interplay between HIF-1α and the molecular clock in chondrocytes, in states of both health and disease, while also incorporating creative interpretations. We explore diverse hypotheses regarding the intricate interactions among these pathways and propose relevant therapeutic strategies for cartilage disorders such as osteoarthritis.

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Section: Future Perspectives and Research Directionsmentioning

confidence: 99%

Hypoxic Conditions Modulate Chondrogenesis through the Circadian Clock: The Role of Hypoxia-Inducible Factor-1α

Juhász,

Hajdú,

Kovács

et al. 2024

Cells

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“…Per-ARNT-Sim (PAS) domains can be found in proteins from all kingdoms of life. Proteins containing PAS domains in the animal kingdom are involved in cellular responses to hypoxia [1,2], hormonal signalling cascades [3], circadian cycles [2,4,5], synaptic plasticity [6] and xenobiotic responses [7]. Additionally, PAS domains are found within several transcription regulators [8,9].…”

Section: Introductionmentioning

confidence: 99%

Molecular Forces Governing the Biological Function of Per-Arnt-Sim-B (PAS-B) Domains: A Comparative Computational Study

et al. 2021

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Per-Arnt-Sim (PAS) domains are evolutionarily-conserved regions found in proteins in all living systems, involved in transcriptional regulation and the response to hypoxic and xenobiotic stress. Despite having low primary sequence similarity, they show an impressively high structural conservation. Nonetheless, understanding the underlying mechanisms that drive the biological function of the PAS domains remains elusive. In this work, we used molecular dynamics simulations and bioinformatics tools in order the investigate the molecular characteristics that govern the intrinsic dynamics of five PAS-B domains (human AhR receptor, NCOA1, HIF1α, and HIF2α transcription factors, and Drosophila Suzukii (D. Suzukii) juvenile hormone receptor JHR). First, we investigated the effects of different length of N and C terminal regions of the AhR PAS-B domain, showing that truncation of those segments directly affects structural stability and aggregation propensity of the domain. Secondly, using the recently annotated PAS-B located in the methoprene-tolerant protein/juvenile hormone receptor (JHR) from D. Suzukii, we have shown that the mutation of the highly conserved “gatekeeper” tyrosine to phenylalanine (Y322F) does not affect the stability of the domain. Finally, we investigated possible redox-regulation of the AhR PAS-B domain by focusing on the cysteinome residues within PAS-B domains. The cysteines in AhR PAS-B are directly regulating the dynamics of the small molecule ligand-gating loop (residues 305 to 326). In conclusion, we comprehensibly described several molecular features governing the behaviour of PAS-B domains in solution, which may lead to a better understanding of the forces driving their biological functions.

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“…Per-Arnt-Sim (PAS) domains occur in proteins from all kingdoms of life. In animals, proteins containing PAS domains are regulating responses to hypoxia, 1,2 circadian rhythms, [2][3][4] hormonal stimuli, 5 synaptic plasticity, 6 memory, 7 and xenobiotic stress, 8 exerting their activity as transcription factors and nuclear receptor coactivators. The PAS domain is also a part of the hERG potassium channel.…”

Section: Introductionmentioning

confidence: 99%

Druggability assessment of mammalian Per–Arnt–Sim [PAS] domains using computational approaches

et al. 2019

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Interplay between environmentally modulated feedback loops – hypoxia and circadian rhythms – two sides of the same coin?

Cited by 6 publications

References 20 publications

Hypoxic Conditions Modulate Chondrogenesis through the Circadian Clock: The Role of Hypoxia-Inducible Factor-1α

Hypoxic Conditions Modulate Chondrogenesis through the Circadian Clock: The Role of Hypoxia-Inducible Factor-1α

Molecular Forces Governing the Biological Function of Per-Arnt-Sim-B (PAS-B) Domains: A Comparative Computational Study

Druggability assessment of mammalian Per–Arnt–Sim [PAS] domains using computational approaches

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