Journal
JOURNAL OF CELLULAR BIOCHEMISTRY
Volume 104, Issue 6, Pages 2228-2240Publisher
WILEY
DOI: 10.1002/jcb.21779
Keywords
p19(ARF); Mtgr1; colon; tumor suppressor
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Funding
- NCI NIH HHS [R01 CA112005, R01 CA064140-07, P30 CA068485, R01-CA112005, CA68485, R01-CA64140, R01 CA064140] Funding Source: Medline
- NIDDK NIH HHS [P30 DK058404, K08 DK080221, K08 DK080221-01, 5P30DK58404-03] Funding Source: Medline
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P19(ARF) is a tumor suppressor that is frequently deleted in human cancer. It lies at chromosome 9p21 and shares exons 2 and 3 with p16(ink4a), which is also inactivated by these cancer-associated deletions. The canonical pathway by which P19(ARF) is thought to suppress tumorigenesis through activation of the p53 tumor suppressor. In response to hyperproliferative signals, such as expression of oncogenes, p19(ARF) is induced and binds to the MDM2 ubiquitin ligase, sequestering it in the nucleolus to allow the accumulation of p53. However, P19(ARF) also has MDM2 and p53 independent functions. In human colon cancer, P19(ARF) is only rarely deleted, but it is more frequently silenced by DNA promoter methylation. Here we show that inactivation of P19(ARF) in mice increases the number of cycling cells in the crypts of the colonic epithelium. Moreover, inactivation of P19(ARF) exacerbated the ulceration of the colonic epithelium caused by dextran sodium sulfate (DSS). These effects were similar to those observed in mice lacking myeloid translocation gene-related-1 (Mtgr1), and mice lacking both of these genes showed an even greater sensitivity to DSS. Surprisingly, inactivation of P19(ARF) restored the loss of the secretory lineage in mice deficient in Mtgr1, suggesting an additional role for p19(ARF) in the small intestinal epithelium.
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