The Circadian Clock in Cancer Development and Therapy - Progress in Molecular Biology and Translational Science - page 250

promoters. 364,365 GREs are found in the regulatory regions of Per1 , Per2 ,
Bmal1 ,and Cry1 genes, 366-368 and both CRY1 and 2 directly interact with
GR in a ligand-dependent fashion to modulate the transcriptional activity
of GR. 188 Administration of dexamethasone, a glucocorticoid analog,
phase-shifts the molecular clock in cultured rat-1 fibroblasts as well as in
mouse livers. Although unable to phase-shift the SCN clock, dexamethasone
can resynchronize about 60% of the circadian transcriptome in the livers of
SCN-lesioned mice via at least in part directly phase-shifting the molecular
clock. 31,366 Adrenalectomy results in deregulation of the core clock genes,
and desynchronization and dampening of the molecular clock in multiple
peripheral tissues. 369
The SNS directly innervates all peripheral tissues by releasing norepi-
nephrine (NE) to target adrenergic receptors (ADRs) on cell membranes.
It also controls the production and secretion of epinephrine (EPI) from
the adrenal medulla, which then targets all cells expressing ADRs in the
body via blood circulation. 370 ADR b 2 is the best-studied ADR that
responds to ligand binding by activating c-AMP response element-binding
protein (CREB), which then interacts with the c-AMP response element
(CRE) in promoters to regulate gene transcription. Both Per1 and Per2 con-
tain CREs in the promoters and are among the immediate early genes acti-
vated by CREB in cultured primary osteoblasts, NIH3T3 cells, and mouse
liver slides in response to administration of isoproterenol, a synthetic agonist
of ADR b 2, EPI, or NE in vitro and in mouse livers after intraperitoneal
injection of adrenalines in vivo . 29,149,371 Loss of function in Per1 and Per2
or sympathectomy abolishes SNS-induced peripheral clock activation in
affected tissues in rodents. 29,149,372-375
The activation of ADR b is followed by b -Arrestin-mediated receptor
desensitization. As multifunctional scaffold proteins, the interaction of
b -Arrestins with ADR b leads to activation of other signal transduction path-
ways including the MAPK, Ras/ERK, JNK, nuclear factor kappa-light-
chain-enhancer of activated B cells (NF- k B), b -Catenin, CaM kinases II,
phosphatidylinositide 3-kinases/protein kinase B/mammalian target of
rapamycin (PI3K/AKT/mTOR), Janus kinase 3/signal transducer and acti-
vator of transcription (JAK3/STAT), insulin-like growth factor 1 (IGF-1),
and MDM2-p53 pathways. 134,376-380 Glucocorticoid signaling also cross-
talks with pathways controlled by NF- k B, b -Catenin, PI3K, and epidermal
growth factor receptor. 381-385 The pathways stimulated by glucocorticoid
and ADR b signaling modulate not only the molecular clock at transcrip-
tional and posttranslational levels but also cell proliferation, apoptosis, and