Features | Partner Sites | Information | LinkXpress
Sign In
PURITAN MEDICAL
GLOBETECH PUBLISHING LLC
Demo Company

Failure of Mutant Menin Protein to Block Hedgehog Signaling Triggers a Type of Endocrine Cancer

By BiotechDaily International staff writers
Posted on 09 May 2013
Image: Endocrine Tumor Syndrome. Inhibition of Hedgehog signaling in a MEN1 mouse model results in decreased islet cell proliferation. Immunofluorescence for BrdUrd and insulin in pancreas of Men1-excised mice fed with either vehicle control (left) or Erivedge/GDC-0449 (right) for four weeks at a dose of 100 mg/kg twice daily (Photo courtesy of Dr. Xianxin Hua, and Dr. Buddha Gurung, Perelman School of Medicine, University of Pennsylvania).
Image: Endocrine Tumor Syndrome. Inhibition of Hedgehog signaling in a MEN1 mouse model results in decreased islet cell proliferation. Immunofluorescence for BrdUrd and insulin in pancreas of Men1-excised mice fed with either vehicle control (left) or Erivedge/GDC-0449 (right) for four weeks at a dose of 100 mg/kg twice daily (Photo courtesy of Dr. Xianxin Hua, and Dr. Buddha Gurung, Perelman School of Medicine, University of Pennsylvania).
Mutations in the gene that encodes the protein menin cause a hereditary cancer syndrome called MEN1 (multiple endocrine neoplasia type 1) due to the inability of the mutant menin protein to block the oncogenic effects of enhanced Hedgehog signaling.

The Hedgehog signaling pathway transmits information to embryonic cells required for proper development. Different parts of the embryo have different concentrations of Hedgehog signaling proteins. The pathway takes its name from its polypeptide ligand, an intercellular signaling molecule called Hedgehog (Hh) found in fruit flies of the genus Drosophila. Hh is one of Drosophila's segment polarity-gene products, involved in establishing the basis of the fly body plan. The molecule remains important during later stages of embryogenesis and metamorphosis, and diseases associated with the malfunction of this pathway include basal cell carcinoma.

Individuals with MEN1 are at a substantially increased risk of developing neuroendocrine tumors, including cancer of the pancreatic islet cells that secrete insulin.

Investigators at the University of Pennsylvania (Philadelphia, USA) performed DNA microarray analysis studies on murine pancreatic islets with mutated menin genes. They reported in the April 15, 2013, online edition of the journal Cancer Research that elimination of menin enhanced pro-proliferative and oncogenic Hedgehog signaling activity.

The investigators showed that menin functioned by physically interacting with a second protein, PRMT5 (protein arginine methyltransferase 5). The menin-PRMT5 complex bound to the promoter of the Gas1 (growth arrest-specific protein 1) gene, where PRMT5 functioned as an epigenetic inhibitor by methylating histone proteins, which inhibited gene transcription. The Gas1 protein normally promoted Hedgehog signaling, and thus by inhibiting Gas1 expression, menin and PRMT5 effectively blocked the pathway's ability to induce cell proliferation. In MEN1 cells mutant menin failed to bind to PRMT5, and Gas1 continued to enhance Hedgehog signaling.

In another set of experiments the investigators treated a mouse model of human MEN1 syndrome with the Hedgehog pathway inhibitor Erivedge, a drug approved by the [US] Food and Drugs Administration for the treatment of metastatic or locally advanced basal cell carcinoma. They reported that the drug reduced proliferation of tumor cells and lowered blood insulin levels.

"Because we show in this mouse tumor model that we can significantly suppress proliferation of tumor cells in pancreatic islets and that we can reduce the higher insulin levels with a drug, which was just clinically approved to be safe, that naturally raises the question of whether, in patients who have mutation in this gene or enhanced Hedgehog signaling, this drug can improve patient symptoms to reduce tumor progression or insulinemia," said senior author Dr Xianxin Hua, associate professor of cancer biology at the University of Pennsylvania.

Related Links:

University of Pennsylvania



Channels

Drug Discovery

view channel
Image: Cancer cells were treated with a control (left) and the overstimulating compound MCB-613 (right) (Photo courtesy of Dr. Lei Wang, Baylor University College of Medicine).

Drug Candidate Propels Cancer Cells into Fatal Overdrive

A candidate drug that destroys cancer cells by stimulating them to produce more proteins than the cells can actually process was shown to kill a wide variety of cancer cells in culture and to inhibit tumor... Read more

Lab Technologies

view channel
Image: The Synergy Neo2 Multi-Mode Reader recently received Cisbio HTRF certification (Photo courtesy of BioTek Instruments Inc.).

High-Speed Multimode Microplate Reader Receives Homogenous Time-Resolved Fluorescence Certification

A new high-performance, high-speed microplate reader has received HTRF (homogenous time-resolved fluorescence) accreditation that certifies that it complies with standards for detection set by a major... Read more

Business

view channel

Innovative Microbial Diagnostics Developer Acquired by Biomedical Giant

A biotech company noted for its development of innovative products in the field of molecular microbiology diagnostics has been acquired by one of the world's largest biomedical corporations. GeneWEAVE BioSciences, Inc.(Los Gatos, CA, USA) and Roche (Basel, Switzerland) have announced that Roche will be purchasing the... Read more
 
Copyright © 2000-2015 Globetech Media. All rights reserved.