The intestinal epithelium is in a dynamic equilibrium of proliferation, differentiation and apoptosis along the crypt-villus gradien. Stem cells reside in the crypt base and are referred to as crypt base columnar (CBC) cells, which are actively proliferating, and a second, quiescent population resides in he +4 position. The interrelationship between these two populations of stem cells is the focus of much attention. Normal intestinal homeostasis is disturbed during states of infection, inflammation and malignant transformation (adenomatous polyps, colorectal cancer). Our work has introduced and elucidated the role of mRNA binding proteins in intestinal/colonic epithelial homeostasis and aberrations in homeostasis, including hyperproliferation, altered metabolism and transformation. LIN28B, a mRNA binding protein, also critical in embryonic stem cells, post- transcriptionally regulates the let-7 microRNA family and results in suppression of differentiation. In turn, Let-7 microRNAs have diverse mRNA targets, including what we have elaborated upon, namely Igf2 mRNA binding protein-1 (IMP-), an mRNA binding protein originally identified as a translational modulator of c-Myc and Igf2 mRNAs. We have demonstrated that LIN28B modulates intestinal/colonic proliferation, migration, invasion and growth. Additionally, IMP-1, as revealed by us, displays crosstalk with K-Ras and modulates colon cancer cell survival. The overall hypothesis of this proposal is that LIN28b promotes intestinal/colonic epithelial proliferation, growth and transformation through Let-7 dependent mechanisms as well as through Let-7 independent mechanisms involving the targeting of mRNAs involved in cell metabolism, facilitating growth and transformation. Furthermore, IMP-1 is an invaluable executor of th LIN28B-Let-7 mediated actions. We will pursue this hypothesis through the following interrelated Specific Aims: (1) To elucidate the inter-relationship between LIN28B and c-MYC in intestinal epithelial biology~ (2) To evaluate the Let-7 dependent vs. the Let-7 independent effects of LIN28B in intestinal crypt biology, Paneth cell identity and transformation~ and (3) To evaluate the biological properties of IMP-1 in intestinal epithelial biology. In aggregate our innovative studies reveal new insights into how the LIN28B-Let-7-IMP-1 axis modulates intestinal epithelial homeostasis and aberrations, and starts to unravel new pathways, which in turn might have translational applications (diagnosis, prognosis and therapy).

Public Health Relevance

The intestinal/colonic epithelia undergo an exquisite program of proliferation and differentiation that is continuously renewed, and yet, subjct to insults such as infection, inflammation and transformation. This project seeks to understand and elucidate how LIN28b and IMP-1, two RNA binding proteins, affect stem cells, differentiation and transformation, using state of the art in vitro and in vivo approaches. The insights gained will hopefully have translational applications in diagnosis, prognosis and therapy in patients.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
High Priority, Short Term Project Award (R56)
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Clinical, Integrative and Molecular Gastroenterology Study Section (CIMG)
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Hamilton, Frank A
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University of Pennsylvania
Internal Medicine/Medicine
Schools of Medicine
United States
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Mongroo, Perry S; Noubissi, Felicite K; Cuatrecasas, Miriam et al. (2011) IMP-1 displays cross-talk with K-Ras and modulates colon cancer cell survival through the novel proapoptotic protein CYFIP2. Cancer Res 71:2172-82
Hanlon, Linda; Avila, Jacqueline L; Demarest, Renée M et al. (2010) Notch1 functions as a tumor suppressor in a model of K-ras-induced pancreatic ductal adenocarcinoma. Cancer Res 70:4280-6