Reference SummaryLee S, PLoS One 2010;5(6):e10995

Title

 Disrupting circadian homeostasis of sympathetic signaling promotes tumor development in mice.

Authors

 Lee S; Donehower LA; Herron AJ; Moore DD; Fu L

Journal

 PLoS One

Volume

 5

Issue

 6

Year

 2010

Pages

 e10995

Abstract

 BACKGROUND: Cell 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 FINDINGS: Mice 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/SIGNIFICANCE: Tumor 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.

Links

 J:161808 – MGI References
20539819 – National Library of Medicine/PubMed

Strain Notes

Strain Note
C57BL/6 This wild-type cohort was pooled from the wild-type littermates of several different crosses.
C57BL/6-Cry1tm1Asn These mice are the product of an intercross between strains on a congenic C57BL/6 background.
C57BL/6-Cry1tm1Asn Cry2tm1Asn These mice are the product of an intercross between strains on a congenic C57BL/6 background.
C57BL/6-Per1tm1Brd Per2tm1Brd These mice are the product of an intercross between strains on a congenic C57BL/6 background.

Models
Strain Model Name Treatment Agent(s) Organ Affected Frequency Model Details
C57BL/6 Bone osteosarcoma Bone

0
C57BL/6 Bone osteosarcoma
  • gamma-radiation
 Bone

0
C57BL/6 Bone osteosarcoma
  • gamma-radiation
  • jet-lag light cycle
 Bone

3.7
B6.129-Bmal1tm1Bra/+ Bone osteosarcoma Bone

0
B6.129-Bmal1tm1Bra/+ Bone osteosarcoma
  • gamma-radiation
 Bone

0
B6.129-Bmal1tm1Bra Bone osteosarcoma Bone

0
B6.129-Bmal1tm1Bra Bone osteosarcoma
  • gamma-radiation
 Bone

0
B6.129-Bmal1tm1Bra Bone osteosarcoma
  • gamma-radiation
  • jet-lag light cycle
 Bone

0
B6.129-Per2tm1Ccl Bone osteosarcoma Bone

0
B6.129-Per2tm1Ccl Bone osteosarcoma
  • gamma-radiation
 Bone

3.03
B6.129-Per2tm1Ccl Bone osteosarcoma
  • gamma-radiation
  • jet-lag light cycle
 Bone

5.71
C57BL/6-Cry1tm1Asn Bone osteosarcoma Bone

0
C57BL/6-Cry1tm1Asn Bone osteosarcoma
  • gamma-radiation
 Bone

4.76
C57BL/6-Cry1tm1Asn Cry2tm1Asn Bone osteosarcoma Bone

0
C57BL/6-Cry1tm1Asn Cry2tm1Asn Bone osteosarcoma
  • gamma-radiation
 Bone

3.33
C57BL/6-Cry1tm1Asn Cry2tm1Asn Bone osteosarcoma
  • gamma-radiation
  • jet-lag light cycle
 Bone

6.06
C57BL/6-Per1tm1Brd Per2tm1Brd Bone osteosarcoma Bone

0
C57BL/6-Per1tm1Brd Per2tm1Brd Bone osteosarcoma
  • gamma-radiation
 Bone

2.13
C57BL/6-Per1tm1Brd Per2tm1Brd Bone osteosarcoma
  • gamma-radiation
  • jet-lag light cycle
 Bone

4.08
B6.129S7-Trp53tm1Brd Bone osteosarcoma
  • jet-lag light cycle
 Bone

observed
C57BL/6-Cry1tm1Asn Cry2tm1Asn Intestine tumor
  • gamma-radiation
  • jet-lag light cycle
 Intestine

observed
C57BL/6-Per1tm1Brd Per2tm1Brd Intestine tumor
  • gamma-radiation
  • jet-lag light cycle
 Intestine

observed
C57BL/6-Cry1tm1Asn Cry2tm1Asn Kidney tumor
  • gamma-radiation
  • jet-lag light cycle
 Kidney

observed
C57BL/6-Per1tm1Brd Per2tm1Brd Kidney tumor
  • gamma-radiation
  • jet-lag light cycle
 Kidney

observed
C57BL/6 Leukocyte lymphoma Leukocyte

5.56
C57BL/6 Leukocyte lymphoma
  • gamma-radiation
 Leukocyte

10.23
C57BL/6 Leukocyte lymphoma
  • gamma-radiation
  • jet-lag light cycle
 Leukocyte

27.78
C57BL/6 Leukocyte lymphoma
  • gamma-radiation
  • jet-lag light cycle
 Salivary gland

observed
B6.129-Bmal1tm1Bra/+ Leukocyte lymphoma Leukocyte

12.9
B6.129-Bmal1tm1Bra/+ Leukocyte lymphoma
  • gamma-radiation
 Leukocyte

33.33
B6.129-Bmal1tm1Bra/+ Leukocyte lymphoma
  • gamma-radiation
  • jet-lag light cycle
 Leukocyte

observed
B6.129-Bmal1tm1Bra/+ Leukocyte lymphoma
  • gamma-radiation
  • jet-lag light cycle
 Salivary gland

observed
B6.129-Bmal1tm1Bra Leukocyte lymphoma Leukocyte

0
B6.129-Bmal1tm1Bra Leukocyte lymphoma
  • gamma-radiation
 Leukocyte

8.33
B6.129-Bmal1tm1Bra Leukocyte lymphoma
  • gamma-radiation
  • jet-lag light cycle
 Leukocyte

7.69
B6.129-Bmal1tm1Bra Leukocyte lymphoma
  • gamma-radiation
  • jet-lag light cycle
 Salivary gland

observed
B6.129-Per2tm1Ccl Leukocyte lymphoma Leukocyte

13.33
B6.129-Per2tm1Ccl Leukocyte lymphoma
  • gamma-radiation
 Leukocyte

33.33
B6.129-Per2tm1Ccl Leukocyte lymphoma
  • gamma-radiation
  • jet-lag light cycle
 Leukocyte

40
C57BL/6-Cry1tm1Asn Leukocyte lymphoma Leukocyte

10
C57BL/6-Cry1tm1Asn Leukocyte lymphoma
  • gamma-radiation
 Leukocyte

23.81
C57BL/6-Cry1tm1Asn Cry2tm1Asn Leukocyte lymphoma Leukocyte

13.33
C57BL/6-Cry1tm1Asn Cry2tm1Asn Leukocyte lymphoma
  • gamma-radiation
 Leukocyte

23.33
C57BL/6-Cry1tm1Asn Cry2tm1Asn Leukocyte lymphoma
  • gamma-radiation
  • jet-lag light cycle
 Leukocyte

36.36
C57BL/6-Cry1tm1Asn Cry2tm1Asn Leukocyte lymphoma
  • gamma-radiation
  • jet-lag light cycle
 Salivary gland

observed
C57BL/6-Per1tm1Brd Per2tm1Brd Leukocyte lymphoma Leukocyte

17.5
C57BL/6-Per1tm1Brd Per2tm1Brd Leukocyte lymphoma
  • gamma-radiation
 Leukocyte

36.17
C57BL/6-Per1tm1Brd Per2tm1Brd Leukocyte lymphoma
  • gamma-radiation
  • jet-lag light cycle
 Leukocyte

38.78
B6.129S7-Trp53tm1Brd Leukocyte lymphoma
  • jet-lag light cycle
 Leukocyte

observed
C57BL/6 Liver hepatocellular carcinoma
  • gamma-radiation
  • jet-lag light cycle
 Liver

observed
B6.129-Bmal1tm1Bra/+ Liver hepatocellular carcinoma
  • gamma-radiation
  • jet-lag light cycle
 Liver

observed
B6.129-Per2tm1Ccl Liver hepatocellular carcinoma Liver

observed
B6.129-Per2tm1Ccl Liver hepatocellular carcinoma
  • gamma-radiation
  • jet-lag light cycle
 Liver

observed
C57BL/6-Cry1tm1Asn Cry2tm1Asn Liver hepatocellular carcinoma Liver

observed
C57BL/6-Cry1tm1Asn Cry2tm1Asn Liver hepatocellular carcinoma
  • gamma-radiation
  • jet-lag light cycle
 Liver

observed
C57BL/6-Per1tm1Brd Per2tm1Brd Liver hepatocellular carcinoma Liver

observed
C57BL/6-Per1tm1Brd Per2tm1Brd Liver hepatocellular carcinoma
  • gamma-radiation
  • jet-lag light cycle
 Liver

observed
C57BL/6 Liver hepatocellular tumor Liver

1.11
C57BL/6 Liver hepatocellular tumor
  • gamma-radiation
 Liver

2.27
C57BL/6 Liver hepatocellular tumor
  • gamma-radiation
  • jet-lag light cycle
 Liver

7.41
B6.129-Bmal1tm1Bra/+ Liver hepatocellular tumor Liver

3.23
B6.129-Bmal1tm1Bra/+ Liver hepatocellular tumor
  • gamma-radiation
 Liver

7.41
B6.129-Bmal1tm1Bra Liver hepatocellular tumor Liver

0
B6.129-Bmal1tm1Bra Liver hepatocellular tumor
  • gamma-radiation
 Liver

0
B6.129-Bmal1tm1Bra Liver hepatocellular tumor
  • gamma-radiation
  • jet-lag light cycle
 Liver

0
B6.129-Per2tm1Ccl Liver hepatocellular tumor Liver

6.67
B6.129-Per2tm1Ccl Liver hepatocellular tumor
  • gamma-radiation
 Liver

9.09
B6.129-Per2tm1Ccl Liver hepatocellular tumor
  • gamma-radiation
  • jet-lag light cycle
 Liver

14.29
C57BL/6-Cry1tm1Asn Liver hepatocellular tumor Liver

5.0
C57BL/6-Cry1tm1Asn Liver hepatocellular tumor
  • gamma-radiation
 Liver

9.52
C57BL/6-Cry1tm1Asn Cry2tm1Asn Liver hepatocellular tumor Liver

6.67
C57BL/6-Cry1tm1Asn Cry2tm1Asn Liver hepatocellular tumor
  • gamma-radiation
 Liver

13.33
C57BL/6-Cry1tm1Asn Cry2tm1Asn Liver hepatocellular tumor
  • gamma-radiation
  • jet-lag light cycle
 Liver

18.18
C57BL/6-Per1tm1Brd Per2tm1Brd Liver hepatocellular tumor Liver

10
C57BL/6-Per1tm1Brd Per2tm1Brd Liver hepatocellular tumor
  • gamma-radiation
 Liver

17.02
C57BL/6-Per1tm1Brd Per2tm1Brd Liver hepatocellular tumor
  • gamma-radiation
  • jet-lag light cycle
 Liver

24.49
B6.129S7-Trp53tm1Brd Liver hyperplasia
  • jet-lag light cycle
 Liver

observed
C57BL/6 Ovary - Granulosa cell tumor Ovary - Granulosa cell

0
C57BL/6 Ovary - Granulosa cell tumor
  • gamma-radiation
 Ovary - Granulosa cell

1.14
C57BL/6 Ovary - Granulosa cell tumor
  • gamma-radiation
  • jet-lag light cycle
 Ovary - Granulosa cell

3.7
B6.129-Bmal1tm1Bra/+ Ovary - Granulosa cell tumor Ovary - Granulosa cell

3.23
B6.129-Bmal1tm1Bra/+ Ovary - Granulosa cell tumor
  • gamma-radiation
 Ovary - Granulosa cell

3.7
B6.129-Bmal1tm1Bra Ovary - Granulosa cell tumor Ovary - Granulosa cell

0
B6.129-Bmal1tm1Bra Ovary - Granulosa cell tumor
  • gamma-radiation
 Ovary - Granulosa cell

0
B6.129-Bmal1tm1Bra Ovary - Granulosa cell tumor
  • gamma-radiation
  • jet-lag light cycle
 Ovary - Granulosa cell

0
B6.129-Per2tm1Ccl Ovary - Granulosa cell tumor Ovary - Granulosa cell

3.33
B6.129-Per2tm1Ccl Ovary - Granulosa cell tumor
  • gamma-radiation
 Ovary - Granulosa cell

6.06
B6.129-Per2tm1Ccl Ovary - Granulosa cell tumor
  • gamma-radiation
  • jet-lag light cycle
 Ovary - Granulosa cell

8.57
C57BL/6-Cry1tm1Asn Ovary - Granulosa cell tumor Ovary - Granulosa cell

5.0
C57BL/6-Cry1tm1Asn Ovary - Granulosa cell tumor
  • gamma-radiation
 Ovary - Granulosa cell

9.52
C57BL/6-Cry1tm1Asn Cry2tm1Asn Ovary - Granulosa cell tumor Ovary - Granulosa cell

3.33
C57BL/6-Cry1tm1Asn Cry2tm1Asn Ovary - Granulosa cell tumor
  • gamma-radiation
 Ovary - Granulosa cell

6.67
C57BL/6-Cry1tm1Asn Cry2tm1Asn Ovary - Granulosa cell tumor
  • gamma-radiation
  • jet-lag light cycle
 Ovary - Granulosa cell

9.09
C57BL/6-Per1tm1Brd Per2tm1Brd Ovary - Granulosa cell tumor Ovary - Granulosa cell

2.5
C57BL/6-Per1tm1Brd Per2tm1Brd Ovary - Granulosa cell tumor
  • gamma-radiation
 Ovary - Granulosa cell

6.38
C57BL/6-Per1tm1Brd Per2tm1Brd Ovary - Granulosa cell tumor
  • gamma-radiation
  • jet-lag light cycle
 Ovary - Granulosa cell

10.2
C57BL/6-Cry1tm1Asn Cry2tm1Asn Pancreas tumor
  • gamma-radiation
  • jet-lag light cycle
 Pancreas

observed
C57BL/6-Per1tm1Brd Per2tm1Brd Pancreas tumor
  • gamma-radiation
  • jet-lag light cycle
 Pancreas

observed
C57BL/6 Reproductive system (sex not specified) hyperplasia - cystic Reproductive system (sex not specified)

6.67
C57BL/6 Reproductive system (sex not specified) hyperplasia - cystic
  • gamma-radiation
 Reproductive system (sex not specified)

6.82
C57BL/6 Reproductive system (sex not specified) hyperplasia - cystic
  • gamma-radiation
  • jet-lag light cycle
 Reproductive system (sex not specified)

16.67
B6.129-Bmal1tm1Bra/+ Reproductive system (sex not specified) hyperplasia - cystic Reproductive system (sex not specified)

12.9
B6.129-Bmal1tm1Bra/+ Reproductive system (sex not specified) hyperplasia - cystic
  • gamma-radiation
 Reproductive system (sex not specified)

14.81
B6.129-Bmal1tm1Bra Reproductive system (sex not specified) hyperplasia - cystic Reproductive system (sex not specified)

4.35
B6.129-Bmal1tm1Bra Reproductive system (sex not specified) hyperplasia - cystic
  • gamma-radiation
 Reproductive system (sex not specified)

0
B6.129-Bmal1tm1Bra Reproductive system (sex not specified) hyperplasia - cystic
  • gamma-radiation
  • jet-lag light cycle
 Reproductive system (sex not specified)

0
B6.129-Per2tm1Ccl Reproductive system (sex not specified) hyperplasia - cystic Reproductive system (sex not specified)

13.33
B6.129-Per2tm1Ccl Reproductive system (sex not specified) hyperplasia - cystic
  • gamma-radiation
 Reproductive system (sex not specified)

12.12
B6.129-Per2tm1Ccl Reproductive system (sex not specified) hyperplasia - cystic
  • gamma-radiation
  • jet-lag light cycle
 Reproductive system (sex not specified)

20
C57BL/6-Cry1tm1Asn Reproductive system (sex not specified) hyperplasia - cystic Reproductive system (sex not specified)

15
C57BL/6-Cry1tm1Asn Reproductive system (sex not specified) hyperplasia - cystic
  • gamma-radiation
 Reproductive system (sex not specified)

14.29
C57BL/6-Cry1tm1Asn Cry2tm1Asn Reproductive system (sex not specified) hyperplasia - cystic Reproductive system (sex not specified)

20
C57BL/6-Cry1tm1Asn Cry2tm1Asn Reproductive system (sex not specified) hyperplasia - cystic
  • gamma-radiation
 Reproductive system (sex not specified)

20
C57BL/6-Cry1tm1Asn Cry2tm1Asn Reproductive system (sex not specified) hyperplasia - cystic
  • gamma-radiation
  • jet-lag light cycle
 Reproductive system (sex not specified)

30.3
C57BL/6-Per1tm1Brd Per2tm1Brd Reproductive system (sex not specified) hyperplasia - cystic Reproductive system (sex not specified)

10
C57BL/6-Per1tm1Brd Per2tm1Brd Reproductive system (sex not specified) hyperplasia - cystic
  • gamma-radiation
 Reproductive system (sex not specified)

17.02
C57BL/6-Per1tm1Brd Per2tm1Brd Reproductive system (sex not specified) hyperplasia - cystic
  • gamma-radiation
  • jet-lag light cycle
 Reproductive system (sex not specified)

28.57
C57BL/6 Salivary gland hyperplasia Salivary gland

10.0 - 15.0
B6.129S7-Trp53tm1Brd Salivary gland hyperplasia
  • jet-lag light cycle
 Salivary gland

observed
C57BL/6-Cry1tm1Asn Cry2tm1Asn Seminal vesicle hyperplasia - cystic
  • gamma-radiation
  • jet-lag light cycle
 Seminal vesicle

observed
C57BL/6-Per1tm1Brd Per2tm1Brd Seminal vesicle hyperplasia - cystic
  • gamma-radiation
  • jet-lag light cycle
 Seminal vesicle

observed
C57BL/6 Uterus hyperplasia - cystic
  • gamma-radiation
  • jet-lag light cycle
 Uterus

observed
B6.129-Per2tm1Ccl Uterus hyperplasia - cystic Uterus

observed
C57BL/6-Cry1tm1Asn Cry2tm1Asn Uterus hyperplasia - cystic Uterus

observed
C57BL/6-Cry1tm1Asn Cry2tm1Asn Uterus hyperplasia - cystic
  • gamma-radiation
  • jet-lag light cycle
 Uterus

observed
C57BL/6-Per1tm1Brd Per2tm1Brd Uterus hyperplasia - cystic Uterus

observed
C57BL/6-Per1tm1Brd Per2tm1Brd Uterus hyperplasia - cystic
  • gamma-radiation
  • jet-lag light cycle
 Uterus

observed
C57BL/6 (Unspecified organ) angiosarcoma (Unspecified organ)

2.22
C57BL/6 (Unspecified organ) angiosarcoma
  • gamma-radiation
 (Unspecified organ)

4.55
C57BL/6 (Unspecified organ) angiosarcoma
  • gamma-radiation
  • jet-lag light cycle
 (Unspecified organ)

3.7
B6.129-Bmal1tm1Bra/+ (Unspecified organ) angiosarcoma (Unspecified organ)

0
B6.129-Bmal1tm1Bra/+ (Unspecified organ) angiosarcoma
  • gamma-radiation
 (Unspecified organ)

0
B6.129-Bmal1tm1Bra (Unspecified organ) angiosarcoma (Unspecified organ)

0
B6.129-Bmal1tm1Bra (Unspecified organ) angiosarcoma
  • gamma-radiation
 (Unspecified organ)

0
B6.129-Bmal1tm1Bra (Unspecified organ) angiosarcoma
  • gamma-radiation
  • jet-lag light cycle
 (Unspecified organ)

0
B6.129-Per2tm1Ccl (Unspecified organ) angiosarcoma (Unspecified organ)

0
B6.129-Per2tm1Ccl (Unspecified organ) angiosarcoma
  • gamma-radiation
 (Unspecified organ)

0
B6.129-Per2tm1Ccl (Unspecified organ) angiosarcoma
  • gamma-radiation
  • jet-lag light cycle
 (Unspecified organ)

0
C57BL/6-Cry1tm1Asn (Unspecified organ) angiosarcoma (Unspecified organ)

0
C57BL/6-Cry1tm1Asn (Unspecified organ) angiosarcoma
  • gamma-radiation
 (Unspecified organ)

0
C57BL/6-Cry1tm1Asn Cry2tm1Asn (Unspecified organ) angiosarcoma (Unspecified organ)

0
C57BL/6-Cry1tm1Asn Cry2tm1Asn (Unspecified organ) angiosarcoma
  • gamma-radiation
 (Unspecified organ)

0
C57BL/6-Cry1tm1Asn Cry2tm1Asn (Unspecified organ) angiosarcoma
  • gamma-radiation
  • jet-lag light cycle
 (Unspecified organ)

3.03
C57BL/6-Per1tm1Brd Per2tm1Brd (Unspecified organ) angiosarcoma (Unspecified organ)

0
C57BL/6-Per1tm1Brd Per2tm1Brd (Unspecified organ) angiosarcoma
  • gamma-radiation
 (Unspecified organ)

0
C57BL/6-Per1tm1Brd Per2tm1Brd (Unspecified organ) angiosarcoma
  • gamma-radiation
  • jet-lag light cycle
 (Unspecified organ)

0