Endothelial monocyte activating polypeptide-II modulates endothelial cell responses by degrading hypoxia-inducible factor-1alpha through interaction with PSMA7, a component of the proteasome.

Abstract:

:The majority of human tumors are angiogenesis dependent. Understanding the specific mechanisms that contribute to angiogenesis may offer the best approach to develop therapies to inhibit angiogenesis in cancer. Endothelial monocyte activating polypeptide-II (EMAP-II) is an anti-angiogenic cytokine with potent effects on endothelial cells (ECs). It inhibits EC proliferation and cord formation, and it suppresses primary and metastatic tumor growth in-vivo. However, very little is known about the molecular mechanisms behind the anti-angiogenic activity of EMAP-II. In the present study, we explored the molecular mechanism behind the anti-angiogenic activity exerted by this protein on ECs. Our results demonstrate that EMAP-II binds to the cell surface alpha5beta1 integrin receptor. The cell surface binding of EMAP-II results in its internalization into the cytoplasmic compartment where it interacts with its cytoplasmic partner PSMA7, a component of the proteasome degradation pathway. This interaction increases hypoxia-inducible factor 1-alpha (HIF-1alpha) degradation under hypoxic conditions. The degradation results in the inhibition of HIF-1alpha mediated transcriptional activity as well as HIF-1alpha mediated angiogenic sprouting of ECs. HIF-1alpha plays a critical role in angiogenesis by activating a variety of angiogenic growth factors. Our results suggest that one of the major anti-angiogenic functions of EMAP-II is exerted through its inhibition of the HIF-1alpha activities.

journal_name

Exp Cell Res

authors

Tandle AT,Calvani M,Uranchimeg B,Zahavi D,Melillo G,Libutti SK

doi

10.1016/j.yexcr.2009.03.021

subject

Has Abstract

pub_date

2009-07-01 00:00:00

pages

1850-9

issue

11

eissn

0014-4827

issn

1090-2422

pii

S0014-4827(09)00151-7

journal_volume

315

pub_type

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