Tumor Suppression and Circadian Function

Abstract

Circadian clock and cell division cycle are two fundamental biological processes. The circadian clock is the body's molecular time-keeping system, while the cell division cycle regulates development and cellular renewal. The expression of cell cycle genes such as Wee1, Cyclins, and c-Myc are under circadian control and could be directly under the regulation of the circadian transcriptional complex. This complex is composed of heterodimer transactivators CLOCK/NPAS2 with BMAL1, which regulate the transcription of PER1, PER2, CRY1, and CRY2. In turn, the repressors CRY1 and CRY2 turn off the gene expressions of Per1/Per2, Cry1/Cry2 in a periodic manner by acting on the transcriptional complex. Two of these circadian rhythm regulators, PER1 and PER2, have now been linked to DNA damage response pathways in a series of papers that examined gene dosage. Overexpression of either Per1 or Per2 in cancer cells inhibits their neoplastic growth and increases their apoptotic rate. In vivo studies showed that mice deficient in mPer2 showed significant higher incidences of tumor development after genotoxic stress. Loss and dysregulation of Per1 and Per2 gene expression have been found in many types of human cancers. Recent studies demonstrate that both PER1 and PER2 are involved in ATM-Chk1/Chk2 DNA damage response pathways and implicate normal circadian function as a factor in tumor suppression.

Sex and circadian modulatory effects on rat liver as assessed by transcriptome analyses

“…A proto-oncogene protein c-MYC regulates the G 0 to G 1 transition of the cell cycle, and c-Myc has shown to be under circadian regulation in mice (Lee, 2006). Accumulating evidence in mammals reveals that some essential checkpoint elements in the cell cycle, including c-Myc (G 0 /G 1 transition), Cyclin D1 (G 1 /S transition), and WEE1 (G 2 /M transition) are under circadian control (Chen-Goodspeed and Lee, 2007;Hunt and Sassone-Corsi, 2007;Sahar and Sassone-Corsi, 2009). Overall, peripheral circadian clock-mediated tran--lar proliferation and major tissue activities for optimizing local rhythms.…”

Implications of circadian clocks for the rhythmic delivery of cancer therapeutics

“…Mechanisms of cell death result from P53-dependent apoptosis, a process that involves several rhythmic components (Granda et al 2005;Gery et al 2006). Furthermore, both P53 expression and apoptosis were downregulated by circadian disruption through Per2 mutation, Per1 knockout cells or chronic jet lag Gery et al 2006;Chen-Goodspeed & Lee 2007). Thus, the molecular interactions between the circadian clock and the cell cycle and its related apoptosis pathways represent a major determinant of 5-FU chronotolerance (figure 2).…”

“…NPAS2:BMAL1 protein dimers, in particular, play a key role in the molecular clock through the activation of the transcription of the clock genes Per and Cry (Lévi & Schibler 2007;Liu et al 2007). This protein dimer also exerts a negative control on the cell cycle, both through the repression of c-myc and p21, two important players in cellular proliferation and apoptosis, and through the activation of p53, a pro-apoptotic gene, and wee1, whose protein gates cell cycle transition from G2 to mitosis (Matsuo et al 2003;Chen-Goodspeed & Lee 2007;Okyar & Lévi 2008). In proliferating cells, this results in the circadian control of the transition from G1 to S and from G2 to M (Matsuo et al 2003;Lévi et al 2007a).…”

Deregulated expression of the per2 gene in human colorectal carcinoma

“…Seliciclib was most efficient when administered at a time corresponding to the time at which treatment established the proper phase relationship of the oscillating clock genes (13). Several experiments employing cell lines have demonstrated that increased per gene expression leads to the suppression of growth of the transformed cells (17)(18)(19), and per2 has been suggested as a novel therapeutic strategy for the treatment of malignant tumors (20,33).…”