Influence of human p16(INK4) and p21(CIP1) on the in vitro activity of recombinant Plasmodium falciparum cyclin-dependent protein kinases.
The regulatory mechanisms of most cyclin dependent protein kinases (CDKs) are well understood and are highly conserved in eukaryotes. CDKs from the malaria parasite, Plasmodium falciparum, appear to be regulated in a similar manner with regard to cyclin binding and phosphorylation. In order to further understand their regulatory mechanisms, we examined two classes of cyclin dependent kinase inhibitors (CDIs) to inhibit a panel of plasmodial CDKs. We find that Pfmrk and PfPK5 are inhibited by heterologous p21(CIP1) with varying degrees of inhibition. In contrast, PfPK6, a kinase with sequence features characteristic of both a CDK and MAP kinase, is unaffected by this CDI. Furthermore, the CDK4/6 specific CDI, p16(INK4), fails to inhibit these plasmodial CDKs. Taken together, these results suggest that plasmodial CDKs may be regulated by the binding of inhibitory proteins in vivo.
Li
Z
Z
Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, MD 20910-5100, USA.
Le Roch
K
K
Geyer
J A
JA
Woodard
C L
CL
Prigge
S T
ST
Koh
J
J
Doerig
C
C
Waters
N C
NC
D000818:Animals; D001667:Binding, Competitive; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000494:pharmacology*; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics; D016213:Cyclins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics; D010963:Plasmodium falciparum / Q000201:enzymology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D011994:Recombinant Proteins / Q000378:metabolism; D000095043:Cyclin-Dependent Kinase-Activating Kinase
C493956:CDKN1A protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; C406811:PfPK5 protein, Plasmodium falciparum; D015800:Protozoan Proteins; D011994:Recombinant Proteins; C408698:PK6 protein, Plasmodium falciparum; D017346:Protein Serine-Threonine Kinases; D018844:Cyclin-Dependent Kinases; D020928:Mitogen-Activated Protein Kinases; D000095043:Cyclin-Dependent Kinase-Activating Kinase