Circadian Rhythm Of Cell Proliferation Research Articles

The biological clock gene PER1 affects the development of oral squamous cell carcinoma by altering the circadian rhythms of cell proliferation and apoptosis

ABSTRACT Circadian rhythms expressed by the biological clock gene PER1 are aberrantly altered in a variety of tumor cells, including oral squamous cell carcinoma (OSCC); however, their functions and mechanisms are unclear. Here, we found that compared with normal oral epithelial HOK cells, OSCC cells showed altered circadian rhythm characteristics of proliferation, apoptosis and PER1 expression, exhibiting abnormal changes in the 3 dimensions of mesor, amplitude and acrophase. It was further found that in OSCC cells overexpressing PER1 (OE-PER1-SCC15), the circadian rhythm characteristics of cell proliferation, apoptosis, p-AKT and p-mTOR expression were abnormally altered. After adding the AKT activator SC79 to OE-PER1-SCC15 cells, the circadian rhythm characteristics of cell proliferation, apoptosis and p-AKT and p-mTOR expression were altered in opposite ways. In vivo tumorigenic assays demonstrated that overexpression of PER1 inhibited OSCC growth. The circadian rhythm characteristics of cell proliferation and apoptosis, PER1, p-AKT and p-mTOR expression were altered similarly to those observed in vitro. Our findings demonstrate for the first time that PER1 regulates the circadian rhythm of OSCC cell proliferation and apoptosis by altering the circadian rhythm characteristics of the AKT/mTOR pathway. The results have the potential to provide a new strategy for circadian rhythm-based treatment of OSCC.

Disrupting Circadian Homeostasis of Sympathetic Signaling Promotes Tumor Development in Mice

BackgroundCell proliferation in all rapidly renewing mammalian tissues follows a circadian rhythm that is often disrupted in advanced-stage tumors. Epidemiologic studies have revealed a clear link between disruption of circadian rhythms and cancer development in humans. Mice lacking the circadian genes Period1 and 2 (Per) or Cryptochrome1 and 2 (Cry) are deficient in cell cycle regulation and Per2 mutant mice are cancer-prone. However, it remains unclear how circadian rhythm in cell proliferation is generated in vivo and why disruption of circadian rhythm may lead to tumorigenesis.Methodology/Principal FindingsMice lacking Per1 and 2, Cry1 and 2, or one copy of Bmal1, all show increased spontaneous and radiation-induced tumor development. The neoplastic growth of Per-mutant somatic cells is not controlled cell-autonomously but is dependent upon extracellular mitogenic signals. Among the circadian output pathways, the rhythmic sympathetic signaling plays a key role in the central-peripheral timing mechanism that simultaneously activates the cell cycle clock via AP1-controlled Myc induction and p53 via peripheral clock-controlled ATM activation. Jet-lag promptly desynchronizes the central clock-SNS-peripheral clock axis, abolishes the peripheral clock-dependent ATM activation, and activates myc oncogenic potential, leading to tumor development in the same organ systems in wild-type and circadian gene-mutant mice.Conclusions/SignificanceTumor suppression in vivo is a clock-controlled physiological function. The central circadian clock paces extracellular mitogenic signals that drive peripheral clock-controlled expression of key cell cycle and tumor suppressor genes to generate a circadian rhythm in cell proliferation. Frequent disruption of circadian rhythm is an important tumor promoting factor.

A randomized prospective phase-III study comparing the acute oral mucositis of morning vs. afternoon radiotherapy (RT) in patients (pts) with squamous cell carcinoma of the head and neck (SCCHN): NCIC-CTG HN.3

LBA5500 Background: Acute oral mucositis is a dose limiting toxicity in SCCHN pts receiving RT. This study was based on the demonstration of a circadian rhythm in human oral mucosa proliferation with the majority of cells in G1-phase in the morning, S-phase in early afternoon, G2-phase in late afternoon and M-phase at night (Am J Pathol 154:613) with an associated rhythm in clock-gene expression (Am J Pathol 158:1793). Clock-genes control the circadian rhythm in cell proliferation (Cell 111:41, Science 302:255). Since cells in G1 are more radioresistant than cells in G2/M, it was hypothesized that morning RT might lead to less acute mucositis. Methods: A randomized prospective multi-centre phase-III study comparing morning (8–10 AM) vs. afternoon (4–6 PM) RT was completed. Pts with SCCHN receiving radical or postoperative RT encompassing a visible area of oral and/or oropharyngeal mucosa were eligible. Pts were stratified by RT dose (50 Gy/25 fractions (fr) vs. 60 Gy/30 fr vs. 60 Gy/25 fr vs. 66 Gy/33 fr vs. 70 Gy 35 fr), smoking status during RT and centre. Oral mucositis was scored using RTOG criteria and a validated scoring system (Cancer 85:2103). Standardized supportive care for mucositis was allowed. The primary endpoint was the incidence of RTOG grade 3/4 oral mucositis. In order to detect a 50% relative reduction in grade 3/4 mucositis from 35% with afternoon RT to 17.5% with morning RT with a two sided 0.05 significance level and 80% power, a total of 216 pts would be required (assuming a 5% drop out rate). Results: 216 pts were randomized between November-17–1999 and October-18–2004. The current median follow-up is 24 months. Data are being cleaned and the final analysis will be done in March 2005. Data from the primary endpoint and secondary endpoints (time to and duration of grade 2–4 mucositis, treatment delays, quality of life, weight changes, late toxicity, loco-regional control and survival) will be presented. The incidence of mucositis between the two arms will be compared using a Cochran Mantel Haenszel test, a Fishers exact test and a logistic regression model. Conclusions: To be reached after data become available. No significant financial relationships to disclose.

Circadian variation of cell proliferation and cell cycle protein expression in man: clinical implications.

Most physiological, biochemical and behavioural processes have been shown to vary in a regular and predictable periodic manner with respect to time. This review focuses on the circadian rhythm in cell proliferation in bone marrow and gut and how this is associated with a circadian expression of cell cycle proteins in human oral mucosa. The control of circadian rhythms by the suprachiasmatic nuclei and the evolving understanding of the genetic and molecular biology of the circadian clock is outlined. Finally, the potential clinical impact of chronobiology in cancer medicine is discussed.

Daily Regeneration of Rat Adrenocortical Cells: Circadian and Zonal Variations in Cytogenesis

Daily regeneration of rat adrenocortical cells were investigated in terms of circadian and zonal variations by following the cells at the DNA-synthesizing stage. An S-phase was assessed by 5-bromo-2′-deoxyuridine (BrdU) incorporation into the cell-nuclei and/or by visualizing proliferating cell nuclear antigen. The BrdU-positive cells were observed throughout the day mainly in two regions of the adrenal cortex, i.e. the innermost portion of the zona glomerulosa and the outermost portion of the zona fasciculata. Cells only in a latter region showed a distinct circadian rhythm of cell proliferation with a peak at 3–4 a.m. A remarkable rise in the plasma adrenocorticotropin (ACTH) concentration preceded such an increase in the cell proliferation by about 4 hours. This phenomenon could be mimicked by raising the plasma ACTH concentration by the administration of Cortrosyn Z or metyrapone. Angiotensin II-stimuli induced by Na-deficiency increased the proliferation of zona glomerulosa cells in the former region at 6–7p.m without significant effects on that of the zona fasciculata cells in the latter region. Thus at least two sites, which respond differentially to the day/night cycle and circulating hormone levels, exist in rat adrenal cortex being responsible for the cytogenesis in this endocrine organ.

Decreased serum vitamin E levels are associated with age-related macular degeneration

The neocortical ventricular zone is composed of a desynchronized population of proliferating cells. These cells give rise to neurons in the infragranular laminae of neocortex. The present study documents a diurnal rhythmicity of cell proliferation in the ventricular zone and examines the effects of ethanol on this biological clock. Pregnant rats were fed one of 3 diets. They were provided an ethanol-containing (6.7% v/v) liquid diet ad libitum between gestational day (G) 6 and G18, pair-fed an isocalorir liquid control diet, or fed chow and water. Throughout the experiments, the rats were fed either at 08.00 h (E.S.T.) or at 17.00 h (lights on 06.00 to 18.00 h). Rats were given a single injections of bromodeoxyuridine (BrdU) on G17 at one point during a 24 h period (03.00, 06.00, 09.00 h, etc.). The fraction of ventricular cells that incorporated the BrdU was determined using quantitative immunohistochemical methods. Pair-fed control rats (fed at 08.00 or 17.00 h) consumed their food within 4 h of presentation. The ratio of cells passing through the S-phase of the cell cycle changed diurnally; the ratio was highest during the day (0.52 ± 0.01 at 12.00 h) and lowest during the night (0.40 ± 0.02 at 03.00 h). In contrast, the ethanol-fed rats grazed on their food throughout the dark cycle regardless of when the food was presented. The mean peak blood ethanol concentration was 142 ± 13 mg/dl during the dark phase and less than 25 mg/dl during the light phase. Prenatal exposure to ethanol eliminates the fetal circadian rhythm in cell proliferation (mean labeling index of 0.45 ± 0.03). This ethanol-induced alteration demonstrates the resiliency of the developing system; its ability to compensate for traumas that alter the epigenetic control of development.

Chronic alcohol treatment promotes oxidative stress in rat peripheral nerve. Beneficial effects of antioxidants

The neocortical ventricular zone is composed of a desynchronized population of proliferating cells. These cells give rise to neurons in the infragranular laminae of neocortex. The present study documents a diurnal rhythmicity of cell proliferation in the ventricular zone and examines the effects of ethanol on this biological clock. Pregnant rats were fed one of 3 diets. They were provided an ethanol-containing (6.7% v/v) liquid diet ad libitum between gestational day (G) 6 and G18, pair-fed an isocalorir liquid control diet, or fed chow and water. Throughout the experiments, the rats were fed either at 08.00 h (E.S.T.) or at 17.00 h (lights on 06.00 to 18.00 h). Rats were given a single injections of bromodeoxyuridine (BrdU) on G17 at one point during a 24 h period (03.00, 06.00, 09.00 h, etc.). The fraction of ventricular cells that incorporated the BrdU was determined using quantitative immunohistochemical methods. Pair-fed control rats (fed at 08.00 or 17.00 h) consumed their food within 4 h of presentation. The ratio of cells passing through the S-phase of the cell cycle changed diurnally; the ratio was highest during the day (0.52 ± 0.01 at 12.00 h) and lowest during the night (0.40 ± 0.02 at 03.00 h). In contrast, the ethanol-fed rats grazed on their food throughout the dark cycle regardless of when the food was presented. The mean peak blood ethanol concentration was 142 ± 13 mg/dl during the dark phase and less than 25 mg/dl during the light phase. Prenatal exposure to ethanol eliminates the fetal circadian rhythm in cell proliferation (mean labeling index of 0.45 ± 0.03). This ethanol-induced alteration demonstrates the resiliency of the developing system; its ability to compensate for traumas that alter the epigenetic control of development.

Circadian rhythm of cell proliferation in the telencephalic ventricular zone: effect of in utero exposure to ethanol

The neocortical ventricular zone is composed of a desynchronized population of proliferating cells. These cells give rise to neurons in the infragranular laminae of neocortex. The present study documents a diurnal rhythmicity of cell proliferation in the ventricular zone and examines the effects of ethanol on this biological clock. Pregnant rats were fed one of 3 diets. They were provided an ethanol-containing (6.7% v/v) liquid diet ad libitum between gestational day (G) 6 and G18, pair-fed an isocalorir liquid control diet, or fed chow and water. Throughout the experiments, the rats were fed either at 08.00 h (E.S.T.) or at 17.00 h (lights on 06.00 to 18.00 h). Rats were given a single injections of bromodeoxyuridine (BrdU) on G17 at one point during a 24 h period (03.00, 06.00, 09.00 h, etc.). The fraction of ventricular cells that incorporated the BrdU was determined using quantitative immunohistochemical methods. Pair-fed control rats (fed at 08.00 or 17.00 h) consumed their food within 4 h of presentation. The ratio of cells passing through the S-phase of the cell cycle changed diurnally; the ratio was highest during the day (0.52 ± 0.01 at 12.00 h) and lowest during the night (0.40 ± 0.02 at 03.00 h). In contrast, the ethanol-fed rats grazed on their food throughout the dark cycle regardless of when the food was presented. The mean peak blood ethanol concentration was 142 ± 13 mg/dl during the dark phase and less than 25 mg/dl during the light phase. Prenatal exposure to ethanol eliminates the fetal circadian rhythm in cell proliferation (mean labeling index of 0.45 ± 0.03). This ethanol-induced alteration demonstrates the resiliency of the developing system; its ability to compensate for traumas that alter the epigenetic control of development.

Comparison of the circadian rhythm in cell proliferation in corneal epithelium of male rats studied under normal and hypobaric (hypoxic) conditions.

Groups of 20-45-day-old rats maintained on a light (0600-1800)/dark (1800-0600) regimen with food and water available ad libitum were studied for the effect of hypoxic hypoxia on the circadian rhythm of corneal epithelial mitosis and thymidine incorporation. In experiments conducted during the months of September and November, hypoxic hypoxia was accomplished by the exposure of rats to a simulated altitude of 7500 m in one series of experiments, or to a gaseous mixture of 8% oxygen and 92% nitrogen at sea level atmospheric pressure (760 mmHg) in another series of experiments. Controls were included as well. Statistically significant (P less than 0.05) circadian rhythmicity in the corneal mitotic index was substantiated in the control animals with mesor (M) = 12.4%, amplitude (A) = 9.6% and acrophase (phi) of 0911. In the hypoxic hypoxia situation, the mesor and amplitude were depressed to 8.6 and 5.9%, respectively. In control groups, thymidine incorporation was circadian rhythmic with M = 38.5 and A = 11.3 cpm/microns DNA and acrophase of 2255. In the hypoxic hypoxia situation, the mesor was similar to the controls; whereas the amplitude was suppressed to 6.1% and acrophase was phase advanced by about 7 hr. Changes in the circadian rhythm of corneal mitosis and in thymidine incorporation under hypoxic hypoxia can be explained by programmed-in-time energy requirements during the corneal cell regeneration cycle.

Circadian Rhythms Are Suppressed In Hyperproliferative Mouse Epidermis

We examined the chronically hyperproliferative epidermis of the asebia (ab/ab) mouse for circadian rhythms in cell proliferation and in the rate of DNA synthesis, which is related to S phase duration. The curve for the circadian rhythm in cell proliferation for asebia epidermis was suppressed and distorted in comparison to that for BALB/cJ epidermis and in comparison to a composite curve produced by averaging the results from ten other published studies.

Chronobiology in hematology and immunology.

The hematopoietic and the immune systems in all their components are characterized by a multifrequency time structure with prominent rhythms in cell proliferation and cell function in the circadian, infradian, and rhythms in cell proliferation and cell function in the circadian, infradian, and circannual frequency ranges. The circulating formed elements in the peripheral blood show highly reproducible circadian rhythms. The timing and the extent of these rhythms were established in a clinically healthy human population and are shown as chronograms, cosinor summaries and, for some high-amplitude rhythms, as time-qualified reference ranges (chronodesms). Not only the number but also the reactivity of circulating blood cells varies predictably as a function of time as shown for the circadian rhythm in responsiveness of human and murine lymphocytes in vitro to lectin mitogens (phytohemagglutinin and pokeweed mitogen). Some circadian rhythms of hematologic functions appear to be innate and are presumably genetically determined but are modulated and adjusted in their timing by environmental factors, so-called synchronizers. Phase alterations in the circadian rhythms of hematologic parameters of human subjects and of mice by manipulation of the activity-rest or light-dark schedule and/or of the time of food uptake are presented. Characteristically these functions do not change their timing immediately after a shift in synchronizer phase but adapt over several and in some instances over many transient cycles. The circadian rhythm of cell proliferation in the mammalian bone marrow and lymphoid system as shown in mice in vivo and in vitro may lend itself to timed treatment with cell-cycle-specific and nonspecific agents in an attempt to maximize the desired and to minimize the undesired treatment effects upon the marrow. Differences in response, and susceptibility of cells and tissues at different stages of their circadian and circaseptan (about 7-day) rhythms and presumably of cyclic variations in other frequencies are expected to lead to the development of a chronopharmacology of the hematopoietic and immune system. Infradian rhythms of several frequencies have been described for numerous hematologic and immune functions. Some of these, i.e., in the circaseptan frequency range, seem to be of importance for humoral and for cell mediated immune functions including allograft rejection. Infradian rhythms with periods of 19 to 22 days seem to occur in some hematologic functions and are very prominent in cyclic neutropenia and (with shorter periods) in its animal model, the grey collie syndrome.(ABSTRACT TRUNCATED AT 400 WORDS)

Circadian rhythm of cell proliferation in the mouse esophageal epithelium

Circadian rhythm of cell proliferation in the mouse esophageal epithelium

Evidence of a G 1regulation of circadian proliferation in mouse methylcholanthrene-induced sarcomas

In two methylcholanthrene induced sarcomas of C 57BL male mice presenting a circadian proliferation (peak of mitoses at noon and peak of labelling indices between midnight and 4 a.m.), the authors performed per cent labelled mitosis curves every 6th hr during the 8th diurnal period of growth. The G 1 phase showed the most important variation with a significant increase in the groups receiving 3H -thymidine at 2 a.m. The possibility that this periodic variation of G 1 phase regulates the circadian rhythm of cell proliferation is discussed.

Influence of scretin and pentagastrin on the circadian rhythm of cell proliferation in the intestinal mucosa in rats.

The effects of Secretin (3.5 U/100 g) and Pentagastrin (25 μg/l00 g) on cell renewal in jejunal mucosa was studied in male Wistar rats. The labeling index (LI), mitotic index (MI), and histogram of the distribution of labeled cells were measured at 4-hour intervals during 24 h after intraperitoneal injection of hormones and compared with results obtained in control animals. DNA label was obtained by injection of tritiated thymidine (70 μCi/100 g) 30 min before sacrificing the animals. The proliferation of intestinal cells in rats was marked by a circadian rhythm with a nocturnal peak of DNA synthesis. After Pentagastrin, the LI remained high for 16,20, and 24 h after injection, during the time the control levels diminished in the circadian rhythm. The normal MI and the enlargement of the zone of proliferation support the hypothesis of a stimulating effect of gastrin on intestinal cell renewal. After Secretin, the LI peak of the cycle was suppressed and the MI decreased, indicating an inhibiting effect of Secretin on intestinal cell renewal. Secretin and gastrin act as trophic factors on intestinal mucosa and produce opposite effects on cell proliferation.