PHD2: from hypoxia regulation to disease progression

Figures & data

Table 1 PHD2 interactors and targets

PHD2 interactor name	Interaction type	Outcome	References
OS-9	Complex formation with PHD2 or PHD3 and HIFl a	Increased HIFla hydroxylation	48
LIMDI/RHOBTB3	Complex formation with PHD2 and VHL	Increased speed and efficiency of the hydroxylation and consequent ubiquitination of HIFa	49,50
PLDl	Complex formation with PH2, VHL, and HIFla	Accelerated HIFl a degradation under normoxia	5l
AKAP	Complex formation with PH2, VHL, and HIFla	Increased HIFl a degradation	52,53
RUNX3	Interaction with PHD2	Increased HIFla hydroxylation and degradation under hypoxia	54
ING4	Interaction with PHD2	Increased HIFla hydroxylation and degradation under hypoxia	55
p23	Complex formation with PHD2 and HSP90	Facilitated HIFla hydroxylation	56
PHD2 target name		Outcome	References
IKKß		Inhibition of the NFKB activation	57,58
eEF2K		Activation of eEF2 and protein synthesis	59,60
PDE4D		Increased cAMP levels	6l
TR-α		Negative regulation of the calcium/ calmodulin-activated kinase II activation	62
NDRG3		Decreased growth and angiogenesis signaling	63
Rpbl		Proteasomal degradation of Rpbl Stabilization of Rpbl	6465

Abbreviations: PHD, prolyl hydroxylase domain; OS-9, osteosarcoma amplified 9; HIF, hypoxia inducible factor; LIMD1, LIM-domain containing protein; RHOBTB3, rho-related BTB domain-containing protein 3; VHL, von Hippel–Lindau tumor suppressor protein; PLD₁, phospholipase D₁; AKAP, A kinase anchor protein; RUNX3, runt-domain transcription factor; ING4, inhibitor of growth protein 4; eEF2K, eukaryotic elongation factor 2 kinase; HSP, heat shock protein; PDE, phosphodiesterase; cAMP, cyclic adenosine monophosphate; TR-α, thyroid hormone receptor-α; NDRG3, N-myc downstream-regulated gene 3 protein; Rpb1, RNA polymerase II.

Table 2 Summary of the three PHD isoform expression profiles in human tumors using a complete set of published human oncology microarray data

Analysis type by cancer	PHDI		PHD2		PHD3
	Cancer vs normal		Cancer vs normal		Cancer vs normal
Bladder cancer					1
Brain and CNS cancer		4	6		1	3
Breast cancer	10	2	3	3	12	1
Cervical cancer					4
Colorectal cancer		2		14		19
Esophageal cancer				3		3
Gastric cancer	2		2			2
Head and neck cancer			3		3
Kidney cancer	3		8		8	1
Leukemia		3	1	4		4
Liver cancer			3		5
Lung cancer			3		13
Lymphoma			1	1	4	3
Melanoma						3
Myeloma		1	2			2
Other cancer	1	2	2		5	2
Ovarian cancer		1	1	1	2
Pancreatic cancer			1	1	5
Prostate cancer						2
Sarcoma			2		2	2
Significant unique analyses	16	15	37	27	65	45
Total unique analyses	227		357		394

Notes: The number in each cell under “cancer vs normal” corresponds to the amount of cancer types that contains a significantly different level of PHD2 compared to normal corresponding tissue. Thresholds for significance are P=0.05 and fold expression >1.5, considering all gene ranks. Red signifies the PHD overexpression or copy gain in the analyses; blue represents the PHD under expression or copy loss. Intensity of color signifies the best rank of PHD2 in those analyses. Cell color is determined by the best gene rank percentile for the analyses within the cell, as represented below:

Oncomine™ (Compendia Bioscience, Ann Arbor, MI) was used for analysis and visualization.

Abbreviations: PHD, prolyl hydroxylase domain; CNS, central nervous system.