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B. Mark Evers, M.D.
Professor, Department of Surgery

Director, UTMB Cancer Center
Director, Sealy Center for Cancer Cell Biology
Robertson-Poth Distinguished Chair & Professor in General Surgery
email: mevers@utmb.edu

 

Our laboratory is intensely focused on the evaluation of cellular mechanisms leading to the differentiation of the developing intestine and the growth of normal and neoplastic GI tissues.  In addition, the developmental pattern of gene expression in the gut is also a specific area of interest using the human neurotensin gene which is expressed in the gut in a strict spatial and temporal pattern and then re-expressed in various colon cancers.  We have identified cis-acting elements that are responsible for high-level neurotensin gene expression in the gut and postulate that a better understanding of the developmental and age-related changes in neurotensin gene expression will provide a better understanding of the specific cellular mechanisms regulating neurotensin-induced proliferation of gut mucosa.  Novel mechanisms regulating neurotensin gene expression have been identified which include Ras activation, promoter methylation and the combinatorial effect of transcription factors acting on critical proximal elements.  Current studies are assessing signaling pathways regulating neurotensin function as well as mechanisms for neurotensin secretion from intestinal endocrine cells.  A recent genomic analysis identified multiple downstream targets of neurotensin including activation of members of the TGF-b signaling pathway as well as MAPK and NF-kB.  Ongoing studies are currently evaluating the role of these signaling pathways in mediating the effect of neurotensin in normal and neoplastic tissues.  From our studies, the neurotensin gene provides an important endocrine model to better delineate the complex mechanisms leading to differentiation of the gut to a small bowel or colonic phenotype and, in addition, provides a unique paradigm to further investigate the factors regulating the establishment and maintenance of certain cell lineage specific patterns along the cephalocaudal axis of the gut.

Another area of active interest in the laboratory is the better understanding of the signaling pathways which contribute to intestinal cell differentiation.  Our laboratory has examined, in particular, downstream effectors of the Ras signaling pathway.  Current work has identified a critical role for the PI3-K /PTEN pathway in regulating intestinal cell differentiation and downstream targets which include the homeobox gene Cdx-2 and TRAIL, a novel member of the TNF family.  These studies provide a clearer understanding of the crucial signaling mechanisms that contribute to intestinal homeostasis and may provide for novel therapeutic strategies in the treatment of gut neoplasias.

Finally, our laboratory is alsoassessing mechanisms leading to pancreatic inflammation with the hypothesis that pancreaticcancer may arise from chronic inflammatory mechanisms.In a recent seminal study,Ethridge and colleagues in the laboratory have shown that COX-2 is a critical mediator ofpancreatic inflammation and that blocking COX-2, either by chemical inhibitors or geneticdeletion, attenuates pancreatic inflammation associated with acute pancreatitis.Investigators in our laboratory are also focused on a similar inflammatory mechanisms and theirrole in subsequent pancreatic cancer development.These studies may provide a therapeutictarget for the treatment of this devastating cancer.


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Evers BM, Wang X, Zhou Z, Townsend CM Jr, McNeil GP, Dobner PR. Characterization of promoter elements required for cell-specific expression of the neurotensin/neuromedin N gene in a human endocrine cell line.  Molecular and Cellular Biology 15:3870-3881, 1995.

Ding QM, Ko TC, Evers BM.  Caco-2 intestinal cell differentiation is associated with G1 arrest and suppression of CDK2 and CDK4.  American Journal of Physiology 275 (Cell Physiol. 44):C1193-C1200, 1998.

Wang QD, Kim S, Wang XF, Evers BM.  Activation of NF-kB in HT-29 colon cancer cells by inhibition of phosphatidylinositol 3-kinase.  Biochemical and Biophysical Research Communications 273:853-858, 2000.

Wang QD, Ji YS, Wang XF, Evers BM.  Isolation and molecular characterization of the 5-upstream region of the human trail gene.  Biochemical and Biophysical Research Communications 276:466-471, 2000.

Ding QM, Wang QD, Dong Z Evers BM.  Characterization and regulation of E2F activity during intestinal cell differentiation.  American Journal of Physiology (Cell Physiol.) 278:110-117, 2000.

Hellmich MR, Rui XL, Hellmich HL, Fleming RYD, Evers BM, Townsend CM Jr.  Human colorectal cancers express a constitutively active cholecystokinin-B/gastrin receptor that stimulates cell growth. Journal of Biological Chemistry 275:32122-32128, 2000.

Ding QM, Wang QD, Evers BM.  Alterations of MAPK activities associated with intestinal cell differentiation.  Biochemical and Biophysical Research Communications 284:282-288, 2001.

Wang QD, Wang XF, Hernandez A, Kim S, Evers BM.  Inhibition of the phosphatidylinositol 3-kinase pathway contributes to HT29 and Caco-2 intestinal cell differentiation.  Gastroenterology 120:1381-1392, 2001.

Domon-Dell C, Wang QD, Kim S, Kedinger M, Evers BM, Freund J-N.  Stimulation of the intestinal Cdx2 homeobox gene by butyrate in colon cancer cells.  Gut 50:525-529, 2002.

Wang QD, Li N, Wang XF, Kim MM, Evers BM.  Augmentation of sodium butyrate-induced apoptosis by PI3-kinase inhibition in the KM20 human colon cancer cell line.  Clinical Cancer Research 8:1940-1947, 2002.

Kim S, Domon-Dell C, Wang QD, Chung DH, Di Cristofano A, Pandolfi PP, Freund JN, Evers BM.  PTEN and TNF-a regulation of the Cdx-2 homeobox gene through a PI3K, PKB/Akt and NF-kB dependent pathway. Gastroenterology 123:1163-1178, 2002.

Wang QD, Wang X, Hernandez A, Hellmich MR, Gatalica Z, Evers BM.  Regulation of TRAIL expression by the PI3-kinase/Akt/GSK-3 pathway in human colon cancer cells.  Journal of Biological Chemistry 277:36602-36610, 2002.

Ethridge RT, Chung DH, Slogoff M, Ehlers RA, Hellmich MR, Rajaraman S, Saito H, Uchida T, Evers BM.  Cyclooxygenase-2 gene disruption attenuates the severity of acute pancreatitis and pancreatitis-associated lung injury.  Gastroenterology 123:1311-1322, 2002.

Li J, Hellmich MR, Greeley GH, Townsend CM, Evers BM.  Phorbol ester-mediated neurotensin secretion is dependent on the PKCa and d isoforms.  American Journal of Physiology (Gastrointest Liver Physiol):283:G1197-G1206, 2002.

Modur V, Nagarajan R, Evers BM, Milbrandt J.  FOXO proteins regulate TRAIL expression: implications for PTEN mutation in prostate cancer.  Journal of Biological Chemistry 277:47928-47937, 2002.

Sheng H, Shao J, Townsend Jr CM, Evers BM.  Phosphatidylinositol 3-kinase mediates proliferative signals in intestinal epithelial cells. Gut 52:1472-1478, 2003.

Wang QD, Wang XF, Evers BM.  Induction of cIAP-2 in human colon cancer cells through PKCδ/NF-κB.  Journal of Biological Chemistry  278:51091-51099, 2003.

Wang XF, Wang QD, Hu W, Evers BM.  Regulation of phorbol ester-mediated TRAF1 induction in human colon cancer cells through a PKC/RAF/ERK/NF-kappaB-dependent pathway. Oncogene 23:1885-95, 2004.

Kim S, Domon-Dell C, Kang J, Chung DH, Freund JN, Evers BM.  Down-regulation of the tumor suppressor PTEN by the TNFα/NFK/NF-κB pathway is linked to a default IκB-α autoregulatory loop. Journal of Biological Chemistry 279:4285-4291, 2004.

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  Last Revised: January 16, 2008