The goal of the Growth Control and Cancer Group is to investigate molecular alterations in cell cycle control during neoplastic transformation. Specifically, the cellular and molecular mechanisms regulating the G1, S, and G2 phase checkpoint delays induced by various DNA damaging agents are being analyzed in normal diploid human fibroblasts, in human lymphoid cells, in normal breast epithelial cells and in human cells with genetic alterations in cell cycle checkpoint genes and in cancer susceptibility genes, such as the gene mutated in the heritable cancer syndrome ataxia telangiectasia (ATM). Also, ATM-deficient human breast epithelial cell lines and fibroblast lines have been established through siRNA knock-down techniques in order to obtain isogenic populations of these cells that differ only in their levels of ATM. Studies are underway to characterize the function of the ATM and the related ATR protein kinases and the molecular events critical in cell cycle checkpoint signaling following exposures to ionizing radiation (IR) and other environmental stresses. These investigations involve studies of the function and regulation of these protein kinases in cell cycle checkpoint signal transduction pathways. In addition, studies utilizing microarray analyses are ongoing to examine messenger RNA and micro RNA expression in normal cells and in cells from patients with heritable cancer susceptibility syndromes following exposure to environmental insults, with the goal of better understanding critical cellular responses to environmental toxicants and to potentially identify novel genes regulated in response to the insults that may play a critical role in cell survival/death or neoplastic transformation following exposures.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Intramural Research (Z01)
Project #
1Z01ES021157-16
Application #
7327229
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
16
Fiscal Year
2006
Total Cost
Indirect Cost
Name
U.S. National Inst of Environ Hlth Scis
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Ferrucio, Bianca; Tiago, Manoela; Fannin, Richard D et al. (2017) Molecular effects of 1-naphthyl-methylcarbamate and solar radiation exposures on human melanocytes. Toxicol In Vitro 38:67-76
Morales, Abigail J; Carrero, Javier A; Hung, Putzer J et al. (2017) A type I IFN-dependent DNA damage response regulates the genetic program and inflammasome activation in macrophages. Elife 6:
Cui, Yuxia; Palii, Stela S; Innes, Cynthia L et al. (2014) Depletion of ATR selectively sensitizes ATM-deficient human mammary epithelial cells to ionizing radiation and DNA-damaging agents. Cell Cycle 13:3541-50
Palii, Stela S; Cui, Yuxia; Innes, Cynthia L et al. (2013) Dissecting cellular responses to irradiation via targeted disruptions of the ATM-CHK1-PP2A circuit. Cell Cycle 12:1105-18
Hesse, Jill E; Liu, Liwen; Innes, Cynthia L et al. (2013) Genome-wide small RNA sequencing and gene expression analysis reveals a microRNA profile of cancer susceptibility in ATM-deficient human mammary epithelial cells. PLoS One 8:e64779
Zhou, Tong; Chou, Jeff; Zhou, Yingchun et al. (2007) Ataxia telangiectasia-mutated dependent DNA damage checkpoint functions regulate gene expression in human fibroblasts. Mol Cancer Res 5:813-22
Heffernan, Timothy P; Unsal-Kacmaz, Keziban; Heinloth, Alexandra N et al. (2007) Cdc7-Dbf4 and the human S checkpoint response to UVC. J Biol Chem 282:9458-68
Katula, Karen S; Heinloth, Alexandra N; Paules, Richard S (2007) Folate deficiency in normal human fibroblasts leads to altered expression of genes primarily linked to cell signaling, the cytoskeleton and extracellular matrix. J Nutr Biochem 18:541-52
Zhou, Tong; Chou, Jeff W; Simpson, Dennis A et al. (2006) Profiles of global gene expression in ionizing-radiation-damaged human diploid fibroblasts reveal synchronization behind the G1 checkpoint in a G0-like state of quiescence. Environ Health Perspect 114:553-9
Innes, Cynthia L; Heinloth, Alexandra N; Flores, Kristina G et al. (2006) ATM requirement in gene expression responses to ionizing radiation in human lymphoblasts and fibroblasts. Mol Cancer Res 4:197-207

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