Evidence for circadian regulation of activating transcription factor 5 but not tyrosine hydroxylase by the chromaffin cell clock

Endocrinology. 2007 Dec;148(12):5811-21. doi: 10.1210/en.2007-0610. Epub 2007 Sep 6.


In mammals, adrenal medulla chromaffin cells constitute a fundamental component of the sympathetic nervous system outflow, producing most of the circulating adrenaline. We recently found that the rhesus monkey adrenal gland expresses several genes in a 24-h rhythmic pattern, including TH (the rate-limiting enzyme in catecholamine synthesis) and Atf5 (a transcription factor involved in apoptosis and neural cell differentiation) together with the core-clock genes. To examine whether these core-clock genes play a role in adrenal circadian function, we exposed rat pheochromocytoma PC12 cells to a serum shock and found that it triggered rhythmic oscillation of the clock genes rBmal1, rPer1, rRev-erbalpha, and rCry1 and induced the circadian expression of Atf5 but not TH. Furthermore, we found that the CLOCK/brain and muscle Arnt-like protein-1 (BMAL1) heterodimer could regulate Atf5 expression by binding to an E-box motif and repressing activity of its promoter. The physiological relevance of this interaction was evident in Bmal1 -/- mice, in which blunted circadian rhythm of Atf5 mRNA was observed in the liver, together with significantly higher expression levels in both liver and adrenal glands. Although we found no compelling evidence for rhythmic expression of TH in chromaffin cells being regulated by an intrinsic molecular clock mechanism, the Atf5 results raise the possibility that other aspects of chromaffin cell physiology, such as cell survival and cell differentiation, may well be intrinsically regulated.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • ARNTL Transcription Factors
  • Activating Transcription Factors / genetics
  • Activating Transcription Factors / metabolism*
  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • CLOCK Proteins
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism
  • Chromaffin Cells / metabolism*
  • Circadian Rhythm*
  • Cryptochromes
  • Culture Media, Serum-Free / pharmacology
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Electrophoretic Mobility Shift Assay
  • Female
  • Flavoproteins / genetics
  • Flavoproteins / metabolism
  • Gene Expression / drug effects
  • Immunohistochemistry
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mutagenesis, Site-Directed
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Nuclear Receptor Subfamily 1, Group D, Member 1
  • PC12 Cells
  • Period Circadian Proteins
  • Protein Binding
  • Rats
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Trans-Activators / genetics
  • Trans-Activators / metabolism
  • Tyrosine 3-Monooxygenase / genetics
  • Tyrosine 3-Monooxygenase / metabolism*


  • ARNTL Transcription Factors
  • Activating Transcription Factors
  • Arntl protein, mouse
  • Basic Helix-Loop-Helix Transcription Factors
  • Cell Cycle Proteins
  • Cryptochromes
  • Culture Media, Serum-Free
  • DNA-Binding Proteins
  • Flavoproteins
  • Nr1d1 protein, rat
  • Nuclear Proteins
  • Nuclear Receptor Subfamily 1, Group D, Member 1
  • Per1 protein, mouse
  • Per1 protein, rat
  • Per2 protein, rat
  • Period Circadian Proteins
  • Receptors, Cytoplasmic and Nuclear
  • Trans-Activators
  • Tyrosine 3-Monooxygenase
  • CLOCK Proteins
  • Clock protein, mouse
  • Clock protein, rat