cyclin-d1 and Ataxia-Telangiectasia

The molecular basis of sensitivity to therapeutic radiation and chemotherapy is a complex product of cellular and tissue responses. Certain genetic factors can be highlighted as being of special importance in the response of breast cancers to treatment. The breast cancer susceptibility genes, BRCA1 and BRCA2, determine the phenotype of the tumor, with BRCA1- or BRCA2-deficient tumors showing marked sensitivity to ionizing radiation and drugs that produce double-strand breaks. However, the extent to which loss of BRCA1 or BRCA2 function occurs in sporadic cancer has not yet been determined. The ATM protein plays a significant role in determining the response to therapy, but how frequently the function of ATM is disrupted in breast cancer is debated. Although the p53 protein is a major determinant of the response to ionizing radiation and cytotoxic drugs, there is no consistency in how p53 affects the survival of cells, because an impairment of DNA repair is offset by reduced apoptosis. Growth factors that sustain the proliferation of breast cancer cells may impact the response to therapy by inhibiting apoptosis. Loss of cell-cycle checkpoint responses may result in increased sensitivity, particularly if the checkpoint controls the G2 transition. Overexpression of cyclin D, which shortens the duration of the G1 transition, is associated with mild radiation resistance, perhaps by inhibiting apoptosis. Overall, there is much more to be understood in the complex response of breast cancers to therapy, and many other proteins play important roles in the response to treatment. The focus of our investigation is on those genetic alterations in tumors that affect the response to therapy, which will ultimately allow strategies to achieve therapeutic gain.

Topics: Ataxia Telangiectasia; Ataxia Telangiectasia Mutated Proteins; Breast Neoplasms; Cell Cycle Proteins; Cyclin D1; DNA-Binding Proteins; Drug Tolerance; Female; Genes, BRCA1; Genes, BRCA2; Genes, erbB-2; Humans; Protein Serine-Threonine Kinases; Radiation Tolerance; Tumor Suppressor Proteins

Quantitative cytometric studies show that cyclin D1 levels must decline during S phase for proper cell cycle progression, and that cyclin D1 decline follows phosphorylation induced by the checkpoint kinases ataxia telangiectasia mutated (ATM) and ATM and Rad3-related (ATR). ATM is mutated in ataxia telangiectasia (AT), a disease characterized by progressive neurodegeneration. Importantly, neurodegeneration in many cases has been linked to the increased expression of cyclin D1 in neurons leading to inappropriate cell cycle entry. These facts prompted us to test the possibility that ATM normally protects against neural degeneration by suppressing cyclin D1 levels, particularly following genotoxic stress. For this purpose, neural stem cells were induced to differentiate into mature neural cells, including neurons. ATM activity in these cultures was inhibited with a specific chemical inhibitor in the presence or absence of hydrogen peroxide treatment, and the effect on cyclin D1 expression was determined by quantitative, single cell cytometric analyses. As predicted, inhibition of ATM did promote elevation of cyclin D1 in differentiated neurons, particularly under conditions of oxidative stress. The survival of differentiated neurons and of neural stem cells was reduced by such treatments. These data support our suggestion that ATM functions to maintain low levels of cyclin D1 expression in differentiated neurons; and may provide important clues in understanding neural degeneration in general.

Topics: Ataxia Telangiectasia; Ataxia Telangiectasia Mutated Proteins; Cell Cycle Proteins; Cell Death; Cell Line; Cyclin D1; DNA-Binding Proteins; Down-Regulation; Flow Cytometry; Humans; Neurons; Oxidative Stress; Protein Serine-Threonine Kinases; Tumor Suppressor Proteins