Glucocorticoid evoked upregulation of RCAN1-1 in human leukemic CEM cells susceptible to apoptosis
- Yasuko HirakawaEmail Yasuko Hirakawa
- Laura J Nary
- Rheem D Medh
Background: Glucocorticoid hormones (GCs) induce apoptosis of leukemic T-cells by transcriptional regulation via the GC receptor, GR. In the human leukemic CEM cell culture model, RCAN1 has been identified as one of the genes that is specifically upregulated only in the GCsensitive CEM C7-14 cells, but not in the GC-resistant CEM-C1-15 sister cells in correlation with GC-evoked apoptosis. RCAN1 gene encodes two major protein isoforms of the regulator of calcineurin (RCAN1), RCAN1-1 and RCAN1-4 via alternative splicing of exons 1 and 4 respectively, to exons 5-7. Studies reported here evaluated the differential regulation and function of the two transcripts and protein products of RCAN1 by the synthetic GC dexamethasone (Dex), and by modulators of calcium signaling.
Results: Dex selectively upregulates transcript specific for RCAN 1-1 in glucocorticoid (GC)- susceptible human leukemic CEM-C7-14 cells but not in GC-refractory CEM-C1-15 sister cells. Expression of the second major transcript, RCAN1-4, is upregulated by [Ca2+]i inducers, thapsigargin and A23187, but not by Dex, suggesting a mutually exclusive regulatory pathway for both RCAN1 transcripts. GC-mediated upregulation of RCAN1-1 transcript and RCAN1-1 protein was kinase dependent, and was blocked by staurosporine and the p38 MAP kinase inhibitor SB 202190. RCAN1-1 coimmunoprecipitates with calcineurin PP3C and Dex-mediated RCAN1-1 upregulation correlated with reduction in calcineurin PP3C activity.
Conclusion: Data presented here suggest that GCs specifically upregulate RCAN1-1 transcript and protein while inducers of [Ca2+]i selectively upregulate RCAN1-4. GC-mediated increase in RCAN1- 1 abundance and binding possibly inhibits calcineurin activity and modulates apoptosis in CEM-C7- 14 cells.
- Year: 2009
- Volume: 4
- Page/Article: Art. 6
- DOI: 10.1186/1750-2187-4-6
- Submitted on 5 Mar 2009
- Accepted on 2 Sep 2009
- Published on 2 Sep 2009