Aberrant regulation of pVHL levels by microRNA promotes the HIF/VEGF axis in CLL B cells.

Abstract

The molecular mechanism of autocrine regulation of vascular endothelial growth factor (VEGF) in chronic lymphocytic leukemia (CLL) B cells is unknown. Here, we report that CLL B cells express constitutive levels of HIF-1alpha under normoxia. We have examined the status of the von Hippel-Lindau gene product (pVHL) that is responsible for HIF-1alpha degradation and found it to be at a notably low level in CLL B cells compared with normal B cells. We demonstrate that the microRNA, miR-92-1, overexpressed in CLL B cells, can target the VHL transcript to repress its expression. We found that the stabilized HIF-1alpha can form an active complex with the transcriptional coactivator p300 and phosphorylated-STAT3 at the VEGF promoter and recruit RNA polymerase II. This is initial evidence that pVHL, without any genetic alteration, can be regulated by microRNA and explains the aberrant autocrine VEGF secretion in CLL.

• Authors: Asish K Ghosh, Tait D Shanafelt, Amelia Cimmino, Cristian Taccioli, Stefano Volinia, Chang-gong Liu, George A Calin, Carlo M Croce, Denise A Chan, Amato J Giaccia, Charla Secreto, Linda E Wellik, Yean K Lee, Debabrata Mukhopadhyay, Neil E Kay
• Journal: Blood (Blood) Vol. 113 Issue 22 Pg. 5568-74 (May 28 2009) ISSN: 1528-0020 [Electronic] United States
• PMID: 19336759 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Hypoxia-Inducible Factor 1
• MicroRNAs
• STAT3 Transcription Factor
• VEGFA protein, human
• Vascular Endothelial Growth Factor A
• Mixed Function Oxygenases
• p300-CBP Transcription Factors
• Von Hippel-Lindau Tumor Suppressor Protein
• VHL protein, human

Topics

• B-Lymphocytes (metabolism, pathology)
• Cell Culture Techniques
• Cell Nucleus (metabolism)
• Cells, Cultured
• Gene Expression Regulation, Leukemic
• Humans
• Hydroxylation (genetics)
• Hypoxia-Inducible Factor 1 (genetics, metabolism, physiology)
• Leukemia, Lymphocytic, Chronic, B-Cell (genetics, metabolism, pathology)
• MicroRNAs (physiology)
• Mixed Function Oxygenases (metabolism)
• Protein Binding
• Protein Processing, Post-Translational (genetics)
• STAT3 Transcription Factor (metabolism)
• Signal Transduction (genetics)
• Vascular Endothelial Growth Factor A (genetics, metabolism, physiology)
• Von Hippel-Lindau Tumor Suppressor Protein (genetics, metabolism)
• p300-CBP Transcription Factors (metabolism)