Abstract
The p53 tumor-suppressor protein has a key role in the induction of cellular senescence, an important barrier to cancer development. However, very little is known about the physiological mediators of cellular senescence induced by p53. CEACAM1 is an immunoglobulin superfamily member whose expression is frequently lost in human tumors and exhibits tumor-suppressor features in several experimental systems, including Ceacam1 knockout mice. There is currently little understanding of the pathways and mechanisms by which CEACAM1 exerts its tumor-suppressor function. Here we report that CEACAM1 is strongly upregulated during the cellular response to DNA double-strand breaks (DSBs) starting from the lowest doses of DSB inducers used, and that upregulation is mediated by the ataxia telangiectasia mutated (ATM)/p53 pathway. Stable silencing of CEACAM1 showed that CEACAM1 is required for p53-mediated cellular senescence, but not initial cell growth arrest, in response to DNA damage. These findings identify CEACAM1 as a key component of the ATM/p53-mediated cellular response to DNA damage, and as a tumor suppressor mediating cellular senescence downstream of p53.
Highlights
CEACAM1 is an immunoglobulin superfamily member that regulates several cellular functions---including angiogenesis, insulin metabolism and T-cell function---and has features of a tumor suppressor in several experimental systems
We found that CEACAM1 is strongly upregulated during the ATMmediated DNA damage response, that this regulatory effect is mediated by p53 and that induction of CEACAM1 by DNA damage is required for the establishment of cellular senescence, an important barrier to cancer development.5 -- 7
Of expression of CEACAM1 in fibroblasts, frequently used for the the dysregulated activity of cellular oncogenes leads to apoptosis analysis of p53 transcriptional responses, either under normal or cellular senescence, and this is believed to occur as a culture conditions or after treatment with double-strand breaks (DSBs) inducers
Summary
CEACAM1 is an immunoglobulin superfamily member that regulates several cellular functions---including angiogenesis, insulin metabolism and T-cell function---and has features of a tumor suppressor in several experimental systems. The long isoforms encode approximately 70 cytoplasmic amino acids, including several serine, threonine and tyrosine residues that can be phosphorylated and participate in signal transduction This domain is required for CEACAM1’s tumor-suppressor function. We previously reported that functional inhibition of ATM by either stable silencing or pharmacological inhibition selectively transforms human mammary epithelial cells in the absence of exogenous DNA damage, whereas in other human cell types ATM inhibition had no effect.3 These results provided the first in vitro model of human cell transformation by the loss of function of ATM, and showed that human mammary epithelial cells are sensitive to decrease in ATM activity, which is consistent with the increased breast cancer susceptibility of ATM mutation carriers.. We found that CEACAM1 is strongly upregulated during the ATMmediated DNA damage response, that this regulatory effect is mediated by p53 and that induction of CEACAM1 by DNA damage is required for the establishment of cellular senescence, an important barrier to cancer development.5 -- 7
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