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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA104292-01
Application #
6707351
Study Section
Metabolic Pathology Study Section (MEP)
Program Officer
Macleod, Carol L
Project Start
2003-09-30
Project End
2008-08-31
Budget Start
2003-09-30
Budget End
2004-08-31
Support Year
1
Fiscal Year
2003
Total Cost
$356,668
Indirect Cost
Name
Albert Einstein College of Medicine
Department
Pathology
Type
Schools of Medicine
DUNS #
071036636
City
Bronx
State
NY
Country
United States
Zip Code
10461
Tian, Jianmin; Marino, Rebecca; Johnson, Carla et al. (2018) Binding of Drug-Activated CAR/Nr1i3 Alters Metabolic Regulation in the Liver. iScience 9:209-228
Yovchev, Mladen; Jaber, Fadi L; Lu, Zhonglei et al. (2016) Experimental Model for Successful Liver Cell Therapy by Lenti TTR-YapERT2 Transduced Hepatocytes with Tamoxifen Control of Yap Subcellular Location. Sci Rep 6:19275
Tian, Jianmin; Locker, Joseph (2013) Gadd45 in the liver: signal transduction and transcriptional mechanisms. Adv Exp Med Biol 793:69-80
Friedl, Peter; Locker, Joseph; Sahai, Erik et al. (2012) Classifying collective cancer cell invasion. Nat Cell Biol 14:777-83
Locker, Joseph; Segall, Jeffrey E (2011) Breast cancer: the matrix is the message. Am J Pathol 178:966-8
Leoni, Vera P; Ledda-Columbano, Giovanna M; Pibiri, Monica et al. (2011) Expression of c-jun is not mandatory for mouse hepatocyte proliferation induced by two nuclear receptor ligands: TCPOBOP and T3. J Hepatol 55:1069-78
Bhattacharyya, Sanchari; Tian, Jianmin; Bouhassira, Eric E et al. (2011) Systematic targeted integration to study Albumin gene control elements. PLoS One 6:e23234
Tian, Jianmin; Huang, Haiyan; Hoffman, Barbara et al. (2011) Gadd45? is an inducible coactivator of transcription that facilitates rapid liver growth in mice. J Clin Invest 121:4491-502
Severino, Valeria; Locker, Joseph; Ledda-Columbano, Giovanna M et al. (2011) Proteomic characterization of early changes induced by triiodothyronine in rat liver. J Proteome Res 10:3212-24
Columbano, A; Simbula, M; Pibiri, M et al. (2008) Triiodothyronine stimulates hepatocyte proliferation in two models of impaired liver regeneration. Cell Prolif 41:521-31

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