Faculty Profiles

 

Current Research:
Current research interests in my laboratory concern the molecular mechanisms underlying normal and neoplastic epithelial cell growth in the luminal gastrointestinal tract (GI). The GI tract abundantly expresses growth factors many of which bind and activate the EGF receptor present on mucosal cells. We have cloned a zinc finger protein (ZBP-89) that binds to a GC-rich DNA element in the gastrin promoter and confers EGF responsiveness. The full-length protein functions as a repressor of growth factor signals regulating the gastrin promoter. Several other growth related promoters are also regulated by ZBP-89. We have also cloned a ZBP family member, ZBP-99, that is also four-zinc finger Krüppel-type transcription factor. Therefore ZBP proteins appear to be a family of transcriptional regulators. Our recently completed studies indicate that ZBP-89 regulates growth in part by stimulating the cyclin-dependent kinase inhibitor, p21waf1, in a butyrate-dependent manner through recruitment of the histone acetyl transferase p300. Moreover, ZBP-89 triggers growth arrest in a p53-dependent manner by preventing nuclear export of p53. ZBP-89 also induces apoptosis, but this process occurs independent of p53. We have recently discovered that ZBP-89 interacts with another tumor suppressor gene, ATM in a butyrate-dependent manner.  Transgenic expression of ZBP-89 in the small bowel from the villin promoter reduces the number and size of adenomatous polyps in the APCmin mouse.

 

Helicobacter pylori is the major cause of duodenal ulcers and gastric cancer. The organism does not invade the mucosa rather it triggers acute and chronic inflammation as well as gastric atrophy of the gastric mucosa. Subsequently, serum gastrin levels increase and intestinal metaplasia and cancer may develop. The goal of these studies is to use animal and cell culture models to dissect the pathways by which bacterial colonization leads to ulcer development and subsequently cancer. Ongoing projects in the laboratory have revealed that gastrin deficiency mimics the atrophy that occurs during gastric inflammation.  Moreover, these mice develop distal gastric tumors within 10 to 12 months.  Coordinate with the loss of gastrin and development of gastric cancer is the loss of the morphogen sonic hedgehog from the adult gastric corpus and its re-expression in the gastric tumors.  We are currently examining how inflammation regulates sonic hedgehog and in turn what downstream hedgehog targets are relevant to gastric transformation.

 

The transcriptional control of gastrin occurs in two settings, in the stomach, when gastrin gene expression is activated by pH or inflammation; and in cancer, when genes that normally suppress (e.g., menin in ZE) or activate (e.g. ras in colon cancer) transcription are mutated resulting in aberrant overexpression. Studies in my lab have focused on identifying regulatory elements that mediate inducible regulation of the gastrin promoter, identifying the transacting factors that bind these to elements and studying the signal transduction pathways that target these transcription factors. Several DNA elements appear to mediate basal, inducible and tissue specific regulation of the gastrin promoter. Only three families of transcription factors have been reported to bind to most of these elements. My lab has contributed studies directed towards understanding how two zinc finger transcription factor families, Sp1 and ZBP-89, regulate the gastrin promoter. However, the role of these DNA elements in the expression of the gastrin gene in vivo has not been examined. Although inflammation and cytokines regulate gastrin gene expression, it is not clear whether bacterial proteins alone or together with cytokines activate gastrin gene expression. Therefore several questions form the basis for our current studies on the transcriptional control of gastrin. What are the mechanisms by which Sp1 and ZBP-89 regulate the gastrin promoter? How is the human gastrin promoter regulated in vivo under conditions of low acidity and bacterial colonization? Can bacterial proteins exclusive of cytokines regulate the gastrin promoter and by what mechanism? What role does the Th1 predominant cytokine interferon gamma play in the gastrin regulation of gastrin gene expression? Recently we have found that AP1 cooperates with Sp1 to maximize induction of the gastrin promoter.

 

Representative Publications:
Zavros Y, Rathinavelu S, Kao JY, Todisco A, Del Valle J, Weinstock JV, Low MJ, Merchant JL. "Treatment of Helicobacter Gastritis by Interleukin-4 Requires Somatostatin." PNAS, 100: 12944-49, 2003.

 

Bai L and Merchant JL. "Transcription Factor ZBP-89 is Required for STAT1 Constitutive Expression." Nucleic Acid, Res.31: 7264-70, 2003

 

Bai L, Yoon SO, King PD, Merchant JL. "ZBP-89-Induced Apoptosis is p53-Independent and Requires JNK." Cell Death and Differentiation, 11: 663-73, 2004.

 

Smith JL, Freebern WJ, Collins I, DeSiervi A, Montano I, Haggerty CM, McNutt MC, Butscher WG, Dzekunova I, Petersen DW, Kawasaki E, Merchant JL, Gardner K. "Kinetic Profiles of p300 Occupancy In Vivo Predict Common Features of Promoter Structure and Co-Activator Recruitment." PNAS, 101: 11554-9, 2004.

 

Holley-Guthrie EA, Seaman WT, Bhende P, Merchant JL, Kenney SC. "The Epstein-Barr Virus Protein, BMRF1, Activates Gastrin Transcription."  J Virol., 79:745-755, 2005.

 

Shiotani A, Iishi H, Uedo N, Ishiguro S, Tatsuta M, Nakae, Kumamoto M, Merchant JL. "Evidence that Loss of Sonic Hedgehog is an Indicator of Helicobacter Pylori-Induced Atrophic Gastritis Progressing to Gastric Cancer." Am J Gastroenterol., 100:  581-587, 2005.

 

Shiotani A, Iishi H, Uedo N, Ishiguro S, Tatsuta M, Nakae, Kumamoto M, Merchant JL. "Epithelial Cell Turnover in Relation to Ongoing Damage of the Gastric Mucosa of Patients with Early Gastric Cancer:  Increase of Cell Proliferation in Paramalignant Lesions."  J Gastroenterology, 40: 337-344, 2005.

 

Zavros Y, Eaton K, Kang W, Rathinavelu S, Katukuri V,  Kao JY, Samuelson LC, Merchant JL. "Chronic Gastritis in the Hypochlorhydric Gastrin-Deficient Mouse Progresses to Adenocarcinoma." Oncogene, 24:2354-2366, 2005.

 

Rieder G, Tessier A, Qiao XT, Madison B, Gumucio DL, Merchant JL. "Intestinal Metaplasia in the Stomach from  Helicobacter Pylori Correlates with Elk-1 and Serum Response Factor Induction of Villin." J Biol. Chem., 280:  4906-4912, 2005.

 

Kang W, Rathinavelu S., Samuelson LC, Merchant JL. "Expansion of the Gastric Mucous Neck Cell Compartment Correlates with Elevated Levels of Interferon Gamma and MUC6." Lab Invest 85: 702-715, 2005.  Editor’s Comments in same issue: Lab Invest. 85, 593-595,2005.  Also cover photo for Volume 85, issue 5, May 2005.

 

Stepan V, Ramamoorthy S, Nitsche H, Zavros Y, Merchant JL, Todisco A.  "Regulation and Function of the Sonic Hedgehog Signal Transduction Pathway in Isolated Gastric Parietal Cells." J Biol. Chem., 280: 15700-15708, 2005.

 

Rieder G, Merchant JL, Haas R. "Helicobacter Pylori Cag-Type IV Secretion System Facilitates Corpus Colonization to Induce Precancerous Conditions in Mongolian Gerbil." Gastroenterology, 128:  1229-1242, 2005. Editorial Comments by Martin J. Blaser in same issue: Gastroenterology, 128 1512-1515,2005.

 

Merchant JL. "Inflammation, Atrophy Gastric Cancer: Connecting the Molecular Dots."  Gastroenterology, 129: 1079-82, 2005.

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