Oncogenic Kras Expression in Postmitotic Neurons Leads to S100A8-S100A9 Protein Overexpression and Gliosis
Year: 2012
Type: article
Abstract: Previous studies suggest that up-regulation of Ras signaling in neurons promotes gliosis and astrocytoma formation in a cell nonautonomous manner. However, the underlying mechanisms remain unknown. To address this question, we generated compound mice (LSL Kras G12D/+;CamKII-Cre) that express oncogenic Kras from its endogenous locus in postmitotic neurons after birth. These mice developed progressive gliosis, which is associated with hyperactivation of Ras signaling pathways. Microarray analysis identified S100A8 and S100A9 as two secreted molecules that are significantly overexpressed in mutant cortices. In contrast to their usual predominant expression in myeloid cells, we found that overexpression of S100A8 and S100A9 in the mutant cortex is primarily in neurons. This neuronal expression pattern is associated with increased infiltration of microglia in mutant cortex. Moreover, purified S100A8-S100A9 but not S100A8 or S100A9 alone promotes growth of primary astrocytes in vitro through both TLR4 and receptor of advanced glycation end product receptors. In summary, our results identify overexpression of S100A8-S100A9 in neurons as an early step in oncogenic Kras-induced gliosis. These molecules expressed in nonhematopoietic cells may be involved in tumorigenesis at a stage much earlier than what has been reported previously. Background: Hyperactivation of Ras signaling in neurons promotes gliosis and astrocytoma in a cell nonautonomous manner. Results: Neuronal expression of Kras G12D/+ leads to gliosis and overexpression of S100A8-S100A9, which serve as chemoattractants for microglia and growth factors for astrocytes. Conclusion: Overexpression of S100A8-S100A9 in neurons is an early event in Kras G12D-induced gliosis. Significance: S100A8-S100A9 expressed in nonhematopoietic cells may be involved in early stage tumorigenesis.
Source: Journal of Biological Chemistry
Institution: University of Wisconsin–Madison
Language: English
Topic: S100 Proteins and Annexins
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $3,430
Awards: G1308670933, G1332332826, Stress keratin 17 and CD4/8 ratio as prognostic markers in HIV-related anogenital squamous cell precancers and cancers (Biospecimens/Biocohort), G2954138468, G42679306, G625014357, Waisman Intellectual and Developmental Disabilities Research Center, G9000265189, G9000352744, Molecular and Cellular Mechanisms of Chronic Myelomonocytic Leukemia (CMML)
OpenAlex ID: W2083661051