Vasculature Growth - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 640

Fig. 10.2
Hypoxia-responsive
transcription factor JunB is
activated by NF

hypoxia

B triggered
by HIF for hypoxia-induced
VEGF transcription activation
(Source: [ 1273 ]).

κ stabilization activation

NF κ B

HIF

JunB

VEGF

factor [ 1274 ]. Factor CBF also intervenes in synthesis of enzymes such as

collagenase-3, or matrix metallopeptidase MMP13, that degrades the extracellular
matrix, thus liberating space for angiogenesis (CBF

β

β -JunB-MMP13 cascade).

released by T lymphocytes and natural killer cells activates mono-
cytes and macrophages and suppresses the production of VEGFa by macrophages,
as Ifn

Interferon- γ

stimulates transcription of the VegfA gene, but inhibits translation [ 1275 ].
Heterotetrameric RNA-binding Ifn

γ

-activated inhibitor of translation (GAIT) 57 is
a complex that contains ribosomal protein L13a, glutamylprolyl-tRNA synthetase,
synaptotagmin-binding, cytoplasmic, RNA-interacting protein (SynCRIP or het-
erogeneous nuclear ribonucleoprotein hnRNPq), and glyceraldehyde 3-phosphate
dehydrogenase. It binds to mRNA-bound eIF4g and precludes recruitment of the
43S pre-initiation complex. The GAIT complex also prevents translation of acute
phase inflammatory ceruloplasmin (a copper-containing glycoprotein) secreted into
plasma by hepatocytes and in inflammatory sites by stimulated macrophages.
Inhibitor GAIT thus targets pro-inflammatory transcripts and initiate translational
silencing. 58

γ

Placental Growth Factor

Placental growth factor, a VEGF family member, is dispensable for normal morpho-
genesis of the vasculature, but inhibits tumoral angiogenesis and lymphangiogene-
sis, as well as the recruitment of pro-angiogenic macrophages [ 1277 ].

57 A cis-acting RNA element in the 3 UTR of the ceruloplasmin mRNA.
58 Interferon- γ activates a kinase cascade. Death-associated protein kinase DAPK1 activates
DAPK3 that phosphorylates L13a [ 1276 ]. Both Dapk1 and Dapk3 mRNAs contain a 3 UTR GAIT
element. They are thus translationally repressed by the GAIT complex. This negative feedback
prevents complete suppression of translation, thereby allowing a low-level translation of target
transcripts such as VegfA mRNA.