The RET receptor is linked to stress response pathways

RET is a transmembrane receptor required for the development of neuroendocrine and urogenital cell types. Activation of RET has roles in cell growth, migration, or differentiation, yet little is known about the gene expression patterns through which these processes are mediated. We have generated cell lines stably expressing either the RET9 or RET51 protein isoforms and have used these to investigate RET-mediated gene expression patterns by cDNA microarray analyses. As seen for many oncogenes, we identified altered expression of genes associated generally with cell-cell or cell-substrate interactions and up-regulation of tumor-specific transcripts. We also saw increased expression of transcripts normally associated with neural crest or other RET-expressing cell types, suggesting these genes may lie downstream of RET activation in development. The most striking pattern of expression was up-regulation of stress response genes. We showed that RET expression significantly up-regulated the genes for heat shock protein (HSP) 70 family members, HSPA1A, HSPA1B, and HSPA1L. Other members of several HSP families and HSP70-interacting molecules that were associated with stress response protein complexes involved in protein maturation were also specifically up-regulated by RET, whereas those associated with the roles of HSP70 in protein degradation were down-regulated or unaffected. The major mechanism of stress response induction is activation of the heat shock transcription factor HSF1. We showed that RET expression leads to increased HSF1 activation, which correlates with increased expression of stress response genes. Together, our data suggest that RET may be directly responsible for expression of stress response proteins and the initiation of stress response.