Reference SummaryWood PA, Mol Cancer Res 2008 Nov;6(11):1786-93
Title |
Period 2 mutation accelerates ApcMin/+ tumorigenesis. |
Authors |
Wood PA; Yang X; Taber A; Oh EY; Ansell C; Ayers SE; Al-Assaad Z; Carnevale K; Berger FG; Pena MM; Hrushesky WJ |
Journal |
Mol Cancer Res |
Volume |
6 |
Issue |
11 |
Year |
2008 |
Pages |
1786-93 |
Abstract |
Colorectal cancer risk is increased in shift workers with presumed circadian disruption. Intestinal epithelial cell proliferation is gated throughout each day by the circadian clock. Period 2 (Per2) is a key circadian clock gene. Per2 mutant (Per2(m/m)) mice show an increase in lymphomas and deregulated expression of cyclin D and c-Myc genes that are key to proliferation control. We asked whether Per2 clock gene inactivation would accelerate intestinal and colonic tumorigenesis. The effects of PER2 on cell proliferation and beta-catenin were studied in colon cancer cell lines by its down-regulation following RNA interference. The effects of Per2 inactivation in vivo on beta-catenin and on intestinal and colonic polyp formation were studied in mice with Per2 mutation alone and in combination with an Apc mutation using polyp-prone Apc(Min/+) mice. Down-regulation of PER2 in colon cell lines (HCT116 and SW480) increases beta-catenin, cyclin D, and cell proliferation. Down-regulation of beta-catenin along with Per2 blocks the increase in cyclin D and cell proliferation. Per2(m/m) mice develop colonic polyps and show an increase in small intestinal mucosa beta-catenin and cyclin D protein levels compared with wild-type mice. Apc(Min/+)Per2(m/m) mice develop twice the number of small intestinal and colonic polyps, with more severe anemia and splenomegaly, compared with Apc(Min/+) mice. These data suggest that Per2 gene product suppresses tumorigenesis in the small intestine and colon by down-regulation of beta-catenin and beta-catenin target genes, and this circadian core clock gene may represent a novel target for colorectal cancer prevention and control. |
Links |
J:224283 – MGI References 19010825 – National Library of Medicine/PubMed |
| Strain | Model Name | Treatment Agent(s) | Organ Affected | Frequency | Model Details |
|---|---|---|---|---|---|
| C57BL/6 | Intestine - Large Intestine - Colon polyp | Intestine - Large Intestine - Colon |
0 |
||
| C57BL/6-Per2tm1Brd/+ | Intestine - Large Intestine - Colon polyp | Intestine - Large Intestine - Colon |
4.4 |
||
| C57BL/6-Per2tm1Brd | Intestine - Large Intestine - Colon polyp | Intestine - Large Intestine - Colon |
31.25 |
||
| C57BL/6J-ApcMin/+ | Intestine - Large Intestine - Colon polyp | Intestine - Large Intestine - Colon |
observed |
||
| C57BL/6-ApcMin/+ Per2tm1Brd/+ | Intestine - Large Intestine - Colon polyp | Intestine - Large Intestine - Colon |
observed |
||
| C57BL/6-ApcMin/+ Per2tm1Brd | Intestine - Large Intestine - Colon polyp | Intestine - Large Intestine - Colon |
observed |
||
| C57BL/6J-ApcMin/+ | Intestine - Small Intestine - Duodenum polyp | Intestine - Small Intestine - Duodenum |
observed |
||
| C57BL/6-ApcMin/+ Per2tm1Brd/+ | Intestine - Small Intestine - Duodenum polyp | Intestine - Small Intestine - Duodenum |
observed |
||
| C57BL/6-ApcMin/+ Per2tm1Brd | Intestine - Small Intestine - Duodenum polyp | Intestine - Small Intestine - Duodenum |
observed |
||
| C57BL/6J-ApcMin/+ | Intestine - Small Intestine - Ileum polyp | Intestine - Small Intestine - Ileum |
observed |
||
| C57BL/6-ApcMin/+ Per2tm1Brd/+ | Intestine - Small Intestine - Ileum polyp | Intestine - Small Intestine - Ileum |
observed |
||
| C57BL/6-ApcMin/+ Per2tm1Brd | Intestine - Small Intestine - Ileum polyp | Intestine - Small Intestine - Ileum |
observed |
||
| C57BL/6J-ApcMin/+ | Intestine - Small Intestine - Jejunum - Distal polyp | Intestine - Small Intestine - Jejunum - Distal |
observed |
||
| C57BL/6-ApcMin/+ Per2tm1Brd/+ | Intestine - Small Intestine - Jejunum - Distal polyp | Intestine - Small Intestine - Jejunum - Distal |
observed |
||
| C57BL/6-ApcMin/+ Per2tm1Brd | Intestine - Small Intestine - Jejunum - Distal polyp | Intestine - Small Intestine - Jejunum - Distal |
observed |
||
| C57BL/6J-ApcMin/+ | Intestine - Small Intestine - Jejunum - Proximal polyp | Intestine - Small Intestine - Jejunum - Proximal |
observed |
||
| C57BL/6-ApcMin/+ Per2tm1Brd/+ | Intestine - Small Intestine - Jejunum - Proximal polyp | Intestine - Small Intestine - Jejunum - Proximal |
observed |
||
| C57BL/6-ApcMin/+ Per2tm1Brd | Intestine - Small Intestine - Jejunum - Proximal polyp | Intestine - Small Intestine - Jejunum - Proximal |
observed |
||
| C57BL/6J-ApcMin/+ | Intestine - Small Intestine adenoma - microadenoma | Intestine - Small Intestine |
42.3 |
||
| C57BL/6-ApcMin/+ Per2tm1Brd | Intestine - Small Intestine adenoma - microadenoma | Intestine - Small Intestine |
88.9 |
||
| C57BL/6J-ApcMin/+ | Intestine - Small Intestine dysplasia - high grade | Intestine - Small Intestine |
7.7 |
||
| C57BL/6-ApcMin/+ Per2tm1Brd | Intestine - Small Intestine dysplasia - high grade | Intestine - Small Intestine |
14.8 |
||
| C57BL/6J-ApcMin/+ | Intestine - Small Intestine dysplasia - low grade | Intestine - Small Intestine |
low |
||
| C57BL/6-ApcMin/+ Per2tm1Brd | Intestine - Small Intestine dysplasia - low grade | Intestine - Small Intestine |
high |
||
| C57BL/6 | Intestine - Small Intestine polyp | Intestine - Small Intestine |
0 |
||
| C57BL/6-Per2tm1Brd/+ | Intestine - Small Intestine polyp | Intestine - Small Intestine |
0 |
||
| C57BL/6-Per2tm1Brd | Intestine - Small Intestine polyp | Intestine - Small Intestine |
0 |
||
| C57BL/6J-ApcMin/+ | Intestine - Small Intestine polyp | Intestine - Small Intestine |
observed |
||
| C57BL/6-ApcMin/+ Per2tm1Brd/+ | Intestine - Small Intestine polyp | Intestine - Small Intestine |
observed |
||
| C57BL/6-ApcMin/+ Per2tm1Brd | Intestine - Small Intestine polyp | Intestine - Small Intestine |
observed |
||
| C57BL/6J-ApcMin/+ | Spleen hyperplasia | Spleen |
observed |
||
| C57BL/6 | Spleen hyperplasia | Spleen |
0 |
||
| C57BL/6-Per2tm1Brd/+ | Spleen hyperplasia | Spleen |
0 |
||
| C57BL/6-Per2tm1Brd | Spleen hyperplasia | Spleen |
0 |
||
| C57BL/6-ApcMin/+ Per2tm1Brd/+ | Spleen hyperplasia | Spleen |
observed |
||
| C57BL/6-ApcMin/+ Per2tm1Brd | Spleen hyperplasia | Spleen |
observed |