The Circadian Clock in Cancer Development and Therapy - Progress in Molecular Biology and Translational Science - page 240

clock suppresses neoplastic growth by controlling cell proliferation, metab-
olism, senescence, and DNA damage response.
4.1.1 Control of cell proliferation by the molecular clock
Both cell cycle and molecular clocks are operated by interlocked feedback
loops of genes that display periodic and sequential phases of activation
and repression at the transcriptional, posttranscriptional, and posttransla-
tional levels. 200 However, although both are considered as “intracellular
clocks,” a cell cycle clock is fundamentally different from the molecular
clock. First, unlike the molecular clock, the cell cycle clock does not
free-run in normal somatic cells. Therefore, the activities of the peripheral
clock and cell cycle clock can be separated in peripheral tissues in the absence
of proper extracellular mitogenic signals. 173,201-203 Second, the period of a
cell cycle clock is not always fixed as 24 h throughout one's life span. It can
vary from only a few hours in early embryogenesis to 24 h in rapidly
renewing somatic tissues in adult life or indefinitely long due to cellular
senescence. 204-207 Since tumor cells often display the properties of dediffer-
entiation and rapid self-renewal with a cell cycle period shorter than 24 h,
loss of circadian coupling of cell cycle progression in adult life may play a key
role in the initiation of neoplastic growth in vivo .
Circadian variation of mitotic activity in normal human tissues has been
described since 1938. 208 The uncoupling of mitotic rhythm between normal
host tissue and metastasizing cancer was first reported in 1940. 209 It is now
well known that cell proliferation in all the rapidly renewing mammalian
tissues studied follows a diurnal oscillating rhythm under normal physiolog-
ical conditions but is altered in tumors. 75,83,210-216 The coupling of cell
proliferation rhythm between host and tumor has been observed in slow-
growing tumors that show considerably higher levels of DNA synthesis
and mitotic indices than host tissues throughout a 24-h period. 216-218 On
the other hand, an ultradian rhythm less than 24 h in cell proliferation is
often found in metastasizing cancers. 218-221
Genome-wide studies have identified a number of genes controlling
the key steps of initiation, progression, and checkpoint functions of the
cell cycle clock as clock-controlled genes. 7,11-14 These genes encode
proto-oncogenes, tumor suppressors, caspases, cyclins, transcription factors,
and ubiquitin-associated factors essential for regulating cell proliferation and
death. 16-23 Clock-controlled cell cycle regulators are also expressed in all
circadian gene-mutant mouse models studied except that they display signif-
icant changes in expression profiles and amplitudes over a 24-h period,
which is coupled with loss of cell cycle control in adult tissues of mutant