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Ribozyme-mediated compensatory induction of menin-oncosuppressor function in primary fibroblasts from MEN1 patients

E Luzi1, F Marini, I Tognarini

  • 1Department of Internal Medicine, Metabolic Bone Unit, Regional Center for Hereditary Endocrine Tumors, Azienda Ospedaliera Universitaria Careggi, Florence, Italy.

Cancer Gene Therapy
|August 14, 2010
PubMed

Insights

Multiple endocrine neoplasia type 1 (MEN1) involves tumors due to MEN1 gene mutations. Wild-type MEN1 gene expression compensates for mutations post-transcriptionally, suggesting potential RNA-based therapies.

Area of Science:

  • Endocrinology
  • Molecular Biology
  • Genetics

Background:

  • Multiple endocrine neoplasia type 1 (MEN1) syndrome is a genetic disorder characterized by tumors in parathyroid glands, gastroenteropancreatic neuroendocrine cells, and anterior pituitary.
  • The MEN1 gene encodes the menin tumor suppressor protein, and loss of heterozygosity at 11q13 is a hallmark of MEN1-associated tumors.

Purpose of the Study:

  • To investigate the expression of MEN1 mRNA and menin protein in fibroblasts from MEN1 patients with specific mutations.
  • To elucidate the post-transcriptional regulatory mechanisms of MEN1 gene expression in the context of disease.

Main Methods:

  • Analysis of MEN1 mRNA and menin protein expression in fibroblasts from normal individuals and MEN1 patients.
  • Utilizing small-interfering RNA (siRNA) and ribozyme silencing to manipulate MEN1 alleles.
  • Employing gel-retardation assays to study RNA-protein interactions.

Main Results:

  • Full-length menin protein expression was comparable between MEN1 and normal fibroblasts.
  • MEN1 patients showed expression of wild-type MEN1 alleles, with mutant alleles undergoing degradation via nonsense-mediated mRNA decay.
  • Silencing wild-type MEN1 mRNA abolished compensation, while silencing mutant MEN1 mRNA enhanced wild-type expression, indicating post-transcriptional compensation.

Conclusions:

  • MEN1 gene mutation carriers exhibit post-transcriptional upregulation of wild-type menin expression as a compensatory mechanism.
  • These findings provide insights into MEN1 tumorigenesis and support the development of RNA-based therapeutic strategies for MEN1.

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