Mediators of cell cycle arrest or apoptosis in response to cytotoxic drugs, histone deacetylase inhibitors, or serum deprivation

Enumeration of the genes, proteins, and epigenetic factors affecting cell fate and elucidation of the mechanisms through which they function represent a major challenge in the biological sciences. Control of cell proliferation is critical to development, homeostasis, and disease processes.{09}The tumor suppressors retinoblastoma (Rb) and p53 are central regulators in cell proliferation and programmed cell death. Understanding the interaction of histone modification, chromatin remodeling complexes, and cell cycle signaling is relevant to the pathophysiology of disease processes and may reveal new targets for cancer therapy.; Rb is a key regulator of the G1 to S (G1/S) cell cycle transition, and is thought to be required for arrest caused by inhibition of histone deacetylase (HDAC) or deprivation of serum, the molecular mechanisms of which remain elusive. Here it is shown that neither arrest requires the Rb cofactors Brg-1, HDAC1, or prohibitin. Analysis of Brg-1 and Brm-deficient cells demonstrates that HDAC inhibitor-mediated arrest does not require Brg-1 or Brm. These cells do not arrest in response to serum deprivation suggesting a possible requirement for Brm or Brg-1. In contrast, Rb-deficient cells arrest in response to serum deprivation but do not arrest in response to HDAC inhibitor treatment, suggesting that Rb is not required for serum deprivation-mediated arrest. Therefore, cell cycle arrest induced by serum deprivation occurs through a different pathway than does HDAC inhibitor-mediated cell cycle arrest.; p53 is a transcription factor which induces a set of genes including human EI24/PIG8. Expression of EI24/PIG8 is repressed in invasive human cancer, suggesting that EI24/PIG8 may act as a tumor suppressor and account for some of the suppressor activity attributed to p53. As the studies indicating the importance of loss of EI24/PIG8 have been implicated in tumor spreading and apoptosis, it is hypothesized that EI24/PIG8 may be an important mediator of sensitivity to chemotherapy. Here it is demonstrated that suppression of EI24/PIG8 in murine and human cells inhibits the apoptotic response to etoposide treatment. This finding underscores the potential importance of EI24/PIG8 loss in the development of chemotherapeutic resistance in tumors and normal cells, furthermore identifying EI24/PIG8 genetic status/expression level as a potential predictor of etoposide treatment efficacy.