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Menin determines K-RAS proliferative outputs in endocrine cells
- Source :
- The Journal of clinical investigation, vol 124, iss 9
- Publication Year :
- 2014
- Publisher :
- eScholarship, University of California, 2014.
-
Abstract
- Endocrine cell proliferation fluctuates dramatically in response to signals that communicate hormone demand. The genetic alterations that override these controls in endocrine tumors often are not associated with oncogenes common to other tumor types, suggesting that unique pathways govern endocrine proliferation. Within the pancreas, for example, activating mutations of the prototypical oncogene KRAS drive proliferation in all pancreatic ductal adenocarcimomas but are never found in pancreatic endocrine tumors. Therefore, we asked how cellular context impacts K-RAS signaling. We found that K-RAS paradoxically suppressed, rather than promoted, growth in pancreatic endocrine cells. Inhibition of proliferation by K-RAS depended on antiproliferative RAS effector RASSF1A and blockade of the RAS-activated proproliferative RAF/MAPK pathway by tumor suppressor menin. Consistent with this model, a glucagon-like peptide 1 (GLP1) agonist, which stimulates ERK1/2 phosphorylation, did not affect endocrine cell proliferation by itself, but synergistically enhanced proliferation when combined with a menin inhibitor. In contrast, inhibition of MAPK signaling created a synthetic lethal interaction in the setting of menin loss. These insights suggest potential strategies both for regenerating pancreatic β cells for people with diabetes and for targeting menin-sensitive endocrine tumors.
- Subjects :
- MAPK/ERK pathway
Adult
Male
medicine.medical_specialty
Immunology
Enteroendocrine cell
Biology
Medical and Health Sciences
Proto-Oncogene Proteins p21(ras)
Islets of Langerhans
Mice
Pancreatic Cancer
Rare Diseases
Internal medicine
Proto-Oncogene Proteins
medicine
Endocrine system
Animals
Humans
2.1 Biological and endogenous factors
Phosphorylation
Aetiology
Extracellular Signal-Regulated MAP Kinases
Cell Proliferation
Cancer
Oncogene
Cell growth
Tumor Suppressor Proteins
General Medicine
Middle Aged
medicine.anatomical_structure
Endocrinology
Cancer research
Commentary
ras Proteins
Female
Signal transduction
Pancreas
Digestive Diseases
Hormone
Signal Transduction
Subjects
Details
- Database :
- OpenAIRE
- Journal :
- The Journal of clinical investigation, vol 124, iss 9
- Accession number :
- edsair.doi.dedup.....e1b331005986634d034f0cef7f759fc0