A winged helix forkhead (FOXD2) tunes sensitivity to cAMP in T lymphocytes through regulation of cAMP-dependent protein kinase RIalpha.
Forkhead/winged helix (FOX) transcription factors are essential for control of the cell cycle and metabolism. Here, we show that spleens from Mf2-/- (FOXD2-/-) mice have reduced mRNA (50%) and protein (35%) levels of the RIalpha subunit of the cAMP-dependent protein kinase. In T cells from Mf2-/- mice, reduced levels of RIalpha translates functionally into approximately 2-fold less sensitivity to cAMP-mediated inhibition of proliferation triggered through the T cell receptor-CD3 complex. In Jurkat T cells, FOXD2 overexpression increased the endogenous levels of RIalpha through induction of the RIalpha1b promoter. FOXD2 overexpression also increased the sensitivity of the promoter to cAMP. Finally, co-expression experiments demonstrated that protein kinase Balpha/Akt1 work together with FOXD2 to induce the RIalpha1b promoter (10-fold) and increase endogenous RIalpha protein levels further. Taken together, our data indicate that FOXD2 is a physiological regulator of the RIalpha1b promoter in vivo working synergistically with protein kinase B to induce cAMP-dependent protein kinase RIalpha expression, which increases cAMP sensitivity and sets the threshold for cAMP-mediated negative modulation of T cell activation.
Johansson
C Christian
CC
Department of Medical Biochemistry, Institute of Basic Medical Sciences, University of Oslo, N-0317 Oslo, Norway.
Dahle
Maria K
MK
Blomqvist
Sandra Rodrigo
SR
Grønning
Line M
LM
Aandahl
Einar M
EM
Enerbäck
Sven
S
Taskén
Kjetil
K
D001402:B-Lymphocytes / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism / Q000494:pharmacology; D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D051858:Forkhead Transcription Factors; D006801:Humans; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000187:drug effects; D013601:T-Lymphocytes / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism*
D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; D004268:DNA-Binding Proteins; C109562:FOXD2 protein, human; D051858:Forkhead Transcription Factors; C517834:PRKAR1A protein, human; D015534:Trans-Activators; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases