The Circadian Clock in Cancer Development and Therapy - Progress in Molecular Biology and Translational Science - page 248

(CRH), thyrotropin-releasing hormone (TRH), and gonadotropin-
releasing hormone (GnRH). The CRH, TRH, and GnRH control
the activity of NES via the hypothalamic-pituitary-adrenal (HPA) and
hypothalamic-pituitary-gonadal (HPG) axes, while ARC, DMH, LHA,
and PVN control energy expenditure and food intake in response to both
central and peripheral signals. The autonomic paraventricular neurons
(aPVN) directly project to the preganglionic parasympathetic and sympa-
thetic neurons in the brainstem nuclei, dorsal motor nucleus of the vagus
(DMV), and intermediolateral cell columns (IML) of the spinal cord to con-
trol parasympathetic and sympathetic nervous systems. The SCN control of
aPVN neurons leads to a robust circadian oscillation in the function of the
ANS in vivo . The example of SCN control of NES is demonstrated by the
rhythmic activity of the HPA axis. The SCN pacemaker indirectly generates
circadian oscillation of adrenocorticotropic hormone-controlled corticoste-
rone production from the adrenal gland into the blood via control of the
hypothalamic CRH endocrine neurons. 340

In vivo , the ANS innervates all
peripheral tissues except skeletal muscle through G-protein-coupled trans-
membrane receptor (GPCR) in a tissue and/or cell type-specific man-
ner. 341-343 Hormones produced by the pineal gland, and the HPA and
HPG axes, such as melatonin, glucocorticoids, and estrogen, target a wide
range of peripheral tissues, especially the immune, metabolically active, and
reproductive organs. 344-351 The rhythmic intracellular signaling generated
by neurotransmitters and hormones plays an essential role in maintaining
homeostasis of tissue microenvironment ( Fig. 9.2 ) .

4.2.1 Control of G1 cell cycle progression in peripheral tissues by
the central pacemaker
In the central pacemaker, light stimuli activate a cascade of intracellular sig-
nal transduction pathways in the SCN neurons to phase-shift the center
pacemaker including the MAPK, ERK, protein kinase C alpha (PKC a ),
calcium/calmodulin-dependent protein kinases II (CaM kinases II), c-Jun
N-terminal kinase (JNK), c-AMP-PKA, and nitric oxide/c-GMP pathways
that differentially regulate the expression of the immediate early genes c- Fos
and JunB and the core circadian genes Per1 and Per2 in a time-dependent
manner. 352-361 The peripheral clocks do not directly respond to light stim-
uli, but are instead synchronized by cyclic changes in the levels of neuro-
transmitters, growth factors, cytokines, and hormones in the tissue
microenvironment. 340,362,363 Despite the sensitivity of the peripheral clock
to non-SCN cues such as food cues, metabolites, or fluctuation in body