TY - JOUR
T1 - A role for p300/CREB binding protein genes in promoting cancer progression in colon cancer cell lines with microsatellite instability
AU - Ionov, Yurij
AU - Matsui, Sei Ichi
AU - Cowell, John K.
PY - 2004/2/3
Y1 - 2004/2/3
N2 - Our manipulation of the nonsense-mediated decay pathway in microsatellite unstable colon cancer cell lines identified the p300 gene as a potential tumor suppressor in this subtype of cancer. Here, we have demonstrated that not only the p300 gene but also the highly homologous cAMP-response element-binding protein (CREB) binding protein (CBP) gene together are mutated in >85% of microsatellite instability (MSI)+ colon cancer cell lines. A limited survey of primary tumors with MSI+ shows that p300 is also frequently mutated in these cancers, demonstrating that these mutations are not consequences of in vitro growth. The mutations in both genes occur frequently in mononucleotide repeats that generate premature stop codons. Reintroduction of p300 into MSI colon cancer cells could only be supported in the presence of an inactivated CBP gene, suggesting the idea that one or the other function must be inactivated for cancer cell viability, p300 is known to acetylate p53 in response to DNA damage, and when MSI+ cells null for p300 activity are forced to reexpress exogenous p300 cells show slower growth and a flatter morphology. p53 acetylation is increased upon reexpression of p300, suggesting that MSI+ cells constitutively activate the DNA damage response pathway in the absence of DNA-damaging agents. In support of this hypothesis, c-ABL kinase, which is also activated in response to DNA damage, shows higher levels of basal kinase activity in MSI+ cells. These observations suggest that there is a selective growth/survival advantage to mutational inactivation of p300/CBP in cells with inactivated mismatch repair capabilities.
AB - Our manipulation of the nonsense-mediated decay pathway in microsatellite unstable colon cancer cell lines identified the p300 gene as a potential tumor suppressor in this subtype of cancer. Here, we have demonstrated that not only the p300 gene but also the highly homologous cAMP-response element-binding protein (CREB) binding protein (CBP) gene together are mutated in >85% of microsatellite instability (MSI)+ colon cancer cell lines. A limited survey of primary tumors with MSI+ shows that p300 is also frequently mutated in these cancers, demonstrating that these mutations are not consequences of in vitro growth. The mutations in both genes occur frequently in mononucleotide repeats that generate premature stop codons. Reintroduction of p300 into MSI colon cancer cells could only be supported in the presence of an inactivated CBP gene, suggesting the idea that one or the other function must be inactivated for cancer cell viability, p300 is known to acetylate p53 in response to DNA damage, and when MSI+ cells null for p300 activity are forced to reexpress exogenous p300 cells show slower growth and a flatter morphology. p53 acetylation is increased upon reexpression of p300, suggesting that MSI+ cells constitutively activate the DNA damage response pathway in the absence of DNA-damaging agents. In support of this hypothesis, c-ABL kinase, which is also activated in response to DNA damage, shows higher levels of basal kinase activity in MSI+ cells. These observations suggest that there is a selective growth/survival advantage to mutational inactivation of p300/CBP in cells with inactivated mismatch repair capabilities.
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U2 - 10.1073/pnas.0307276101
DO - 10.1073/pnas.0307276101
M3 - Article
C2 - 14732695
AN - SCOPUS:0842320994
SN - 0027-8424
VL - 101
SP - 1273
EP - 1278
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 5
ER -