Our long-term goal is to elucidate the molecular mechanisms for inherited multiple endocrine neoplasia type 1 (MEN1) syndrome and pave the way to develop novel and improved therapy. MEN1 syndrome, characterized by the development of tumors in several endocrine organs, results from a mutation in the MEN1 gene, which encodes a tumor suppressor, menin. As the MEN1 gene is also mutated in ~40% of patients with sporadic neuroendocrine tumors, understanding how menin represses MEN1 tumors will likely provide new insights into how MEN1 tumors and other sporadic endocrine tumors develop. Targeted therapy against MEN1 syndrome is lacking yet highly desirable. Mouse models with ablation of the Men1 gene closely phenocopy MEN1 tumor syndrome, serving as reliable models for studying human menin's tumor suppressing function. Menin is a scaffold protein with multiple functions including regulation of gene transcription. One of menin's roles is to increase expression of anti-proliferative cyclin-dependent kinase inhibitors (CDKIs), p18 and p27. However, little is known as to whether or how menin represses expression of pro-proliferative genes. Our recent studies solved the co-crystal structure in which menin binds JunD, a transcription factor, with a deep pocket, and showed that menin inhibits JunD's function by suppressing its phosphorylation and transcriptional activity. Moreover, acute Men1 excision, in the islets of mice, induced expression of multiple pro-proliferative genes, as well as components of the pro-proliferative Hedgehog (Hh) signaling pathway. Further, we uncovered that menin directly interacts with a transcription-repressing histone arginine methyltransferase in suppressing Hh signaling-related genes. We hypothesize that menin functionally interacts with JunD and the methyltransferase to repress expression of pro-proliferative genes, as well as the genes that promote Hedgehog signaling, and that pharmacological suppression of Hh signaling is effective for treating MEN1 tumors. To test these hypotheses Aim 1 will investigate how menin epigenetically controls expression of cyclin D1 via regulating JunD and the arginine methyltransferase, and its interplay with the menin-regulated CDKI axis in neuroendocrine tumor cells.
Aim 2, will determine the role of the arginine methyltransferase in regulating gene expression, Hedgehog signaling, and beta cell proliferation using conditional knockout mouse models.
Aim 3 will evaluate the impact of experimental therapy on MEN1 tumors by targeting Hh signaling and the CDK axis using mouse MEN1 models. Collectively, these studies will likely unravel a new paradigm for understanding how menin suppresses MEN1 tumor syndrome via crosstalk with a key transcription factor, an epigenetic regulator, and a pro-proliferative signalig pathway. As effective and clinically safe Hh signaling and CDK inhibitors have already been developed, our proposed studies will likely accelerate translation of the basic and mechanistic studies to treating MEN1 tumor syndrome and other MEN1-mutated neuroendocrine tumors with the Hh signaling and CDK inhibitors.

Public Health Relevance

Neuroendocrine neoplasias not only disturb normal functions of the endocrine organs by secreting excessive hormones, but can also lead to mortality. Effective targeted therapy for these types of tumors is lacking. Our studies on how menin epigenetically represses the Hedgehog signaling pathway may provide novel insights into the unique underlying mechanisms of this disease and also prompt clinical trials to treat these types of tumors by targeting the Hedgehog signaling and CDK axis.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
1R01CA178856-01A1
Application #
8696095
Study Section
Molecular and Cellular Endocrinology Study Section (MCE)
Program Officer
Mietz, Judy
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Biology
Type
Schools of Medicine
DUNS #
City
Philadelphia
State
PA
Country
United States
Zip Code
19104