SP1 and p23 play a crucial role in the circadian target gene induction of activated aryl hydrocarbon receptor in human breast cells

The Aryl Hydrocarbon Receptor (AHR) is a crucial mediator of cellular responses upon exposure to environmental pollutants. Initially described as central activator in xenobiotic metabolism, recent research has unveiled additional layers of complexity in AHR function and regulation. The circadian rhythm is a fundamental regulatory process that modulates various physiological processes, including AHR activity. Our recent findings show that AHR-dependent gene induction is subject to circadian rhythmicity. While some studies suggest a circadian AHR gene transcription in various tissues, a comprehensive mechanistic understanding of the circadian AHR regulation remains elusive. This mechanistic study aimed to elucidate the circadian regulation of AHR target gene induction upon dioxin treatment in human breast cells. To acquire a more profound understanding of the intricacies of AHR regulation, we conducted a systematic analysis of the molecular co-factors and their interactions in circadian synchronized cells. Our results show circadian regulation of AHR transcriptional activity at the CYP1A1 promoter upon dioxin treatment. This appears to be orchestrated by the core clock components BMAL1/CLOCK, which directly interact with AHR in circadian synchronized cells. Additionally, we identified SP1 as an important positive and p23 as an essential negative regulator of circadian AHR activity. The understanding of these interactions is crucial for elucidating the molecular relationship between the circadian clock and cellular responses to environmental stimuli. Such knowledge is of vital importance for the application of New Approach Methods (NAMs) as part of a weight-of-evidence (WoE) approach in the next generation of risk assessments.

• Publication year

  2025

• Venue

  Cell Biology and Toxicology

• Publication date

  2025-09-12

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1007/s10565-025-10080-0PMID 40936027PMCID 12426158
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• The complex biology of aryl hydrocarbon receptor activation in cancer and beyond

  2023cited by this paper
• Cryo-EM structure of the cytosolic AhR complex.

  2023cited by this paper
• AHR is a master regulator of diverse pathways in endogenous metabolism

  2022cited by this paper
• Structural insight into the ligand binding mechanism of aryl hydrocarbon receptor

  2022cited by this paper
• The 4th dimension of in vitro systems - Time to level up.

  2022cited by this paper
• Aryl Hydrocarbon Receptor and Its Diverse Ligands and Functions: An Exposome Receptor.

  2021cited by this paper
• Environmental chemicals affect circadian rhythms: An underexplored effect influencing health and fitness in animals and humans.

  2021cited by this paper
• Circadian disruption and human health.

  2021cited by this paper
• 3D Cell Culture Systems: Tumor Application, Advantages, and Disadvantages

  2021cited by this paper
• Clocks, cancer, and chronochemotherapy

  2021cited by this paper
• Chronopharmacology in Therapeutic Drug Monitoring—Dependencies between the Rhythmics of Pharmacokinetic Processes and Drug Concentration in Blood

  2021cited by this paper
• Circadian rhythms: influence on physiology, pharmacology, and therapeutic interventions

  2021cited by this paper
• Differential effects of SUMO1 and SUMO2 on circadian protein PER2 stability and function

  2021cited by this paper
• Mechanisms of circadian clock interactions with aryl hydrocarbon receptor signalling

  2020cited by this paper
• Shift Work and Breast Cancer

  2020cited by this paper
• Molecular mechanisms and physiological importance of circadian rhythms

  2019cited by this paper
• Restoring circadian synchrony in vitro facilitates physiological responses to environmental chemicals.

  2019influential reference
• AhR signaling pathways and regulatory functions

  2018cited by this paper
• p23 protects the human aryl hydrocarbon receptor from degradation via a heat shock protein 90‐independent mechanism

  2018cited by this paper
• Aryl Hydrocarbon Receptor Deficiency Alters Circadian and Metabolic Rhythmicity

  2017cited by this paper
• Berberine Activates Aryl Hydrocarbon Receptor but Suppresses CYP1A1 Induction through miR-21-3p Stimulation in MCF-7 Breast Cancer Cells

  2017cited by this paper
• Circadian Regulation of Benzo[a]Pyrene Metabolism and DNA Adduct Formation in Breast Cells and the Mouse Mammary Gland

  2017cited by this paper
• Transcriptional architecture of the mammalian circadian clock

  2016cited by this paper
• Dosing-Time Makes the Poison: Circadian Regulation and Pharmacotherapy.

  2016cited by this paper
• Sumoylation differentially regulates Sp1 to control cell differentiation

  2014cited by this paper
• Molecular architecture of the mammalian circadian clock.

  2014cited by this paper
• Interplay between Dioxin-Mediated Signaling and Circadian Clock: A Possible Determinant in Metabolic Homeostasis

  2014cited by this paper
• Transcription Factor NF-Y Is a Functional Regulator of the Transcription of Core Clock Gene Bmal1 ♦

  2013cited by this paper
• Molecular components of the Mammalian circadian clock.

  2013cited by this paper
• The aryl hydrocarbon receptor system

  2012cited by this paper
• Ligand Displaces Heat Shock Protein 90 from Overlapping Binding Sites within the Aryl Hydrocarbon Receptor Ligand-binding Domain*

  2011cited by this paper
• Molecular mechanisms of the physiological functions of the aryl hydrocarbon (dioxin) receptor, a multifunctional regulator that senses and responds to environmental stimuli

  2010cited by this paper
• The clock genes period 1 and period 2 mediate diurnal rhythms in dioxin-induced Cyp1A1 expression in the mouse mammary gland and liver.

  2010cited by this paper
• Crosstalk between the AHR signaling pathway and circadian rhythm.

  2009influential reference
• Roles of coactivator proteins in dioxin induction of CYP1A1 and CYP1B1 in human breast cancer cells.

  2009cited by this paper
• Circadian Variations in Rat Liver Gene Expression: Relationships to Drug Actions

  2008cited by this paper
• The arylhydrocarbon receptor repressor (AhRR): structure, expression, and function

  2006cited by this paper
• Circadian Clock Control by SUMOylation of BMAL1

  2005cited by this paper
• Cooperation of heat shock protein 90 and p23 in aryl hydrocarbon receptor signaling

  2004cited by this paper
• Ligand binding and activation of the Ah receptor.

  2002cited by this paper
• The Orphan Nuclear Receptor REV-ERB Controls Circadian Transcription within the Positive Limb of the Mammalian Circadian Oscillator

  2002cited by this paper
• A study on diurnal mRNA expression of CYP1A1, AHR, ARNT, and PER2 in rat pituitary and liver.

  2002cited by this paper
• The hsp90 Chaperone Complex Regulates Intracellular Localization of the Dioxin Receptor

  2001cited by this paper
• The human cytochrome P450 1A1 mRNA is rapidly degraded in HepG2 cells.

  2000cited by this paper
• Identification of a novel mechanism of regulation of Ah (dioxin) receptor function.

  1999cited by this paper
• Daily cycle of bHLH-PAS proteins, Ah receptor and Arnt, in multiple tissues of female Sprague-Dawley rats.

  1998cited by this paper
• CBP/p300 functions as a possible transcriptional coactivator of Ah receptor nuclear translocator (Arnt).

  1997cited by this paper
• Cooperative Interaction between AhR·Arnt and Sp1 for the Drug-inducible Expression of CYP1A1 Gene (*)

  1996cited by this paper
• Two types of normal human breast epithelial cells derived from reduction mammoplasty: phenotypic characterization and response to SV40 transfection.

  1995cited by this paper

• No citing papers are available for this paper.