Partial hepatectomy induces liver regeneration while a number of drugs and hormones induce liver hyperplasia. Both are proliferative responses that promote cancer, but our research has demonstrated that the two responses are independent and initiated by different transcriptional signals. The drug TCPOBOP induces hyperplasia and is also a strong tumor promoter in mice. TCPOBOP is a ligand for the xenobiotic nuclear receptor CAR, which directly activates an immediate-early transcriptional response. Thyroid hormone (T3) binds to a similar nuclear receptor (TR), and both CAR and TR activate very similar response elements in genes. T3 induces hyperplasia in rat liver, but surprisingly, instead of promoting, it suppresses carcinogenesis. We propose that liver regeneration and both hyperplastic agents act through different transcriptional signals that converge on a common set of target genes that lead to proliferation. Each treatment also acts on a unique set of genes that makes the responses different. The effects will be resolved through complementary experimental approaches. Microarray analysis (Aim 1) will determine the common and distinctive patterns of gene regulation that lead to proliferation. Transcriptional studies (Aim 2) will focus on early response genes common to both regeneration and hyperplasia. Experiments will work out novel transcriptional mechanisms for CAR and resolve how the TR and CAR can discriminate regulatory sites. Proliferation and apoptosis (Aim 3) will be studied in both cell culture and knockout animals, to learn how proliferation is controlled, whether hyperplasia protects against apoptosis, and the degree of independence between the two proliferation pathways.
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