Biology Reference
In-Depth Information
Figure 2. Regulation of transcription factor HIF-1: role of oxygen-dependent hydroxylases, co-acti-
vators of transcription and pvHL-targeted proteolysis. CAD = carboxy-terminal transactivation
domain; ODD = oxygen-dependent degradation domain; pro = proline sites; asp = asparagine sites;
P300/CBP = co-activators of transcription; pVHL = von Hippel-Lindau protein; HRE = hypoxia
response element. (Israels LG and Israels ED, 2000. Used with permission of Core Health Services
Inc.)
ment and growth of these tumors [26]. In the von Hippel-Lindau syndrome, the
activity of the tumor suppressor protein pVHL is lost, resulting in the devel-
opment of multiple vascular tumors from unregulated VEGF production and,
in some patients, erythrocytosis due to increased EPO synthesis [27, 28].
The tumor suppressor protein p53 also is a regulator of HIF-1
: p53 recruits
the E3 ligase MDM2 to promote ubiquitin-mediated proteasomal degradation
of HIF-1
α
. Mutations in the p53 gene are present in more than 50% of human
tumors. Loss of p53 may result in HIF-1
α
overexpression, increased VEGF
synthesis, and the angiogenesis associated with some highly vascular renal
tumors [29].
EPO stimulates red cell production, differentiation, and maturation, and
prevents apoptosis. The focus for EPO regulation of erythropoiesis is probably
at the level of the CFU-E. When there is an increase in circulating EPO, the
existing CFU-E respond by proliferation and differentiation; when EPO con-
centrations decrease, CFU-E undergo apoptosis. A stable constitutive EPO
α
