Role of cAMP Signaling in Regulation of Pyruvate Dehydrogenase Kinase 1

Role of cAMP Signaling in Regulation of Pyruvate Dehydrogenase Kinase 1

Celkové hodnotenie

Vedecká práca
Prevedenie (dizajn)
Diskusná interakcia
PoužívateľVedecká prácaDizajnDiskusná interakcia
Mgr. Radivojka Vulić100%100%-
Bc. Patrícia Petáková40%40%-
RNDr. Zora Krivošíková PhD.40%20%-
Bc. Katarína Jurenková60%100%-
Juraj Krajčír80%80%-
ISBN: 978-80-972360-1-4

Role of cAMP Signaling in Regulation of Pyruvate Dehydrogenase Kinase 1

Silvia Radenkovič1 , Mária Bartošová2 , Tereza Goliaš
1 Katedra genetiky, Prírodovedecká fakulta, UK, Bratislava, Slovensko
2 Virologický ustav, BMC, Slovenská akadémia vied

Pyruvate dehydrogenase kinase 1 (PDHK1) is a hypoxia-inducible gene upregulated in cancer [1]. It actively suppresses mitochondrial function by inactivating pyruvate dehydrogenase (PDH) by phosphorylation of all three inhibitory serine sites on PDH (293, 300, 232). PDHKs exist in four tissue-specific isoforms, while only PDHK1 can phosphorylate Ser232 of PDH [2]. It is evident that apart from expression, tumor-associated hypoxia induces PDHK1 activity as assessed by phospho-Ser232-PDH. Ser232 remained unphosphorylated in normoxia, even in the presence of PDHK1, while its phosphorylation gradually increased with the duration of hypoxia and almost completely disappeared post reoxygenation, unlike PDHK1 protein, which was very stable. Hence, hypoxic regulation of PDHK1 activity, more so than its expression, seems to be responsible for acute PDH inhibition in hypoxia. Here we show that cAMP signaling might contribute to this regulation by stimulating PDHK1 activity and partially PDHK1 expression. Protein kinase A (PKA) is a cAMP-dependent kinase, and cAMP levels are elevated in hypoxia [3]. Soluble adenylyl cyclase (sAC) supplies cAMP in mitochondria, while its activity is induced by bicarbonate produced by mitochondrial carbonic anhydrase V (CAV) [4]. H89 (PKA inhibitor) and KH7 (sAC inhibitor) both inhibited hypoxic PDHK1 activity, while overexpression of CAV induced PDHK1 activity in normoxia. Putative PKA-phosphorylation sites were identified on PDHK1 by ScanSite [5]. Apart from activity, cAMP signaling seemed to have influenced PDHK1 expression to a certain extent. Possible CREB (cAMP response element binding protein) binding sights were identified in PDHK1 promoter through CREB Target Gene Database [6] with high probability. Despite our hypothesis needing additional verification and clarification, we believe our findings give useful novel evidence regarding the regulation of PDHK1.


Financial support: VEGA 2/0122/16 (Slovak Scientific Grant Agency) and SASPRO Programme grant 0035/01/02 (SAS and Marie Curie Actions of the EU 7th Framework Programme).


[1] Papandreou I et al. Cell Metab 2006; 3(3):187-97.
[2] Golias T et al. Sci Rep 2016; 6:31146.
[3] Ditte P et al. Cancer Res 2011; 71(24):7558-67.
[4] Chen Y et al. Science 2000; 289(5479):625-8.
[5] ScanSite 2.0 :proteome-wide prediction of cell signaling interactions using short sequence motifs [online]. Available at:
[6] CREB Target Gene Database [online]. Available at: