Diacylglycerol Signaling

14 PKC–PKD Interplay in Cancer
in derepression of gene expression (Bossuyt et al. 2008; Harrison et al. 2006;
Vega et al. 2004). The myocyte enhancer factor-2 (MEF2) is one of the key
downstream transcription factors targeted for repression by class IIa HDACs.
PKD-mediated derepression of MEF2 allows the expression of many genes,
including hypertrophic genes, VEGF-regulated genes and the nuclear receptor Nur77
(Avkiran et al. 2008).
The regulation of HDACs by PKD has been implicated in cardiac remodeling.
PKD can be activated by a variety of hypertrophic stress stimuli in PKC-dependent
and -independent mechanisms in cardiac myocytes (Harrison et al. 2006). Activated
PKD relieves MEF2 repression by phosphorylating HDAC5 and promotes pathological
cardiac remodeling (Harrison et al. 2006; Vega et al. 2004). The role of
PKD1 in cardiac remodeling has been demonstrated in multiple rodent models of
pathological cardiac remodeling. Ectopic expression of constitutively active PKD1
in mouse heart leads to dilated cardiomyopathy (Harrison et al. 2006). Conversely,
cardiac-specific knockout of PKD1 in mice blunts cardiac hypertrophy, fibrosis
caused by pressure overload, chronic adrenergic stimulation, and angiotensin II
treatment and improved cardiac function, indicating an essential role of PKD in
stress-induced pathological cardiac remodeling in vivo (Fielitz et al. 2008). Thus,
PKD1 may represent a promising drug target of multiple heart diseases.
The regulation of class IIa HDACs by PKD has also been implicated in VEGF
signaling in the vascular endothelial cells (Altschmied and Haendeler 2008). VEGF
is the most prominent stimulator of angiogenesis in endothelial cells, a process that
is linked to numerous vascular disorders and cancer. VEGF promotes angiogenesis
by stimulating the proliferation, migration, and survival of endothelial cells. PKD1
has been shown to be activated by VEGF through PLCg/PKCa in endothelial cells
(Wong and Jin 2005). Activated PKD1, similar to that in the heart, phosphorylates
class IIa HDACs, triggering their transport from the nucleus to the cytoplasm, and
derepressing MEF2 transcriptional activity. At least two major class IIa HDACs are
involved in this process, HDAC5 (Ha et al. 2008b) and HDAC7 (Ha et al. 2008a).
HDAC7 in particular is expressed exclusively in endothelial cells. It maintains
vascular integrity by repressing matrix metalloprotease 10 (MMP10) expression in
endothelial cells. Recent studies indicate that VEGF stimulates HDAC7 phosphorylation
and nuclear exclusion by activating PKD1, leading to the expression of
MMPs, MTI-MMP, and MMP10 (Ha et al. 2008a). Other MEF2-regualted genes
involved in angiogenesis have also been identified such as an orphan nuclear receptor –
NR4A1 (Ha et al. 2008b) and early growth response 3 (Egr3) (Liu et al. 2008).
Functionally, it has been shown that HDAC7 phosphorylation by PKD1 is essential
for VEGF-induced endothelial cell proliferation/migration and tube formation/
microvessel sprouting in a mouse aorta ring assay (Ha et al. 2008a). Hence, PKD
is a critical component of VEGF-induced angiogenesis and a potential drug target
for angiogenesis-related diseases, such as macular degeneration, diabetic retinopathy,
and cancer.
Oxidative stress also activates a distinct PKD signaling pathway that involves
Src-Abl and PKCd, leading to the activation of NFkB transcription factor.
Activation of PKD by oxidative stress promotes cell survival (Storz and Toker
291