The goal of this project is to investigate molecular alterations in cell cycle control during neoplastic transformation. Specifically, the molecular mechanisms involved in cell cycle checkpoint responses to exposures to ionizing radiation (IR) are being investigated in normal human fibroblasts and in cells that lack normal function of p53, pRB, or the ataxia telangiectasia (AT) cancer susceptibility gene product. Normal human fibroblasts respond to exposure to IR by rapidly delaying entry into mitosis with an associated strong inhibition of p34cdc2/ cyclinB protein kinase activity. AT fibroblasts exposed to IR show little delay of entry into mitosis or inhibition of kinase activity. The rapid G2 checkpoint response to IR does not require p53, pRB, or p21 function. However, lack of p53 results in a progressively increasing proportion of cells losing their G2 checkpoint function that is strongly correlated with the proportion of cells with chromosomal abnormalities. In at least one case, loss of G2 checkpoint function and the appearance of chromosomal abnormalities was accompanied by a reduction in ATM protein levels. We are particularly interested in the role of the ATM gene product in cell cycle checkpoint responses to exposures to environmental carcinogens and particularly how signals are generated from broken DNA to inactivation of cyclin/ CDK protein kinase complexes. We have developed and characterized several antisera to the ATM protein and are investigating the expression and function of this cancer susceptibility gene product. In addition to aiding our understanding of the process of carcinogenesis, these studies hold great potential for providing insight into the mechanism of action of environmental toxins, and particularly those that have been classified as non-genotoxic carcinogens.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Intramural Research (Z01)
Project #
1Z01ES021157-08
Application #
6106574
Study Section
Special Emphasis Panel (LECM)
Project Start
Project End
Budget Start
Budget End
Support Year
8
Fiscal Year
1998
Total Cost
Indirect Cost
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
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; 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
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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