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Researcher ProfilesCategory: Research Database; Topic: Researcher Profiles
Posted on: Aug 25, 2009; by ming Printer-friendly page
 Guo-fu Hu
 

Guo-fu Hu

Department of Pathology
Harvard Medical School
New Research Building, Room 930G
77 Avenue Louis Pasteur
Boston, MA 02115
Tel: (617) 432-6582
Fax: (617) 432-6580
Email: guofu_hu@hms.harvard.edu

5 postdoctoral fellows, 1 graduate student, 1 research assistant


Our work has been focused on the nuclear function of angiogenin, a 14 kDa angiogenic ribonuclease that is up-regulated in prostate cancer and down-regulated in amyotrophic lateral sclerosis (ALS). We have shown that angiogenin undergoes nuclear translocation in endothelial cells where it binds to the promoter region of rRNA gene and stimulates rRNA transcription. We have also shown that the ribonuclease activity of angiogenin is required for rRNA processing. Because rRNA transcription is necessary for ribosome biogenesis and cell proliferation, our work has shown that angiogenin-stimulated rRNA transcription is a general requirement for cell proliferation and is a crossroad in angiogenesis.

Expression and nuclear translocation of angiogenin are deregulated in cancer cells. Using prostate cancer as an example, we have shown that angiogenin is progressively upregulated during cancer progression and that constitutive nuclear translocation of angiogenin is a causative factor for the development of androgen-independent disease. We demonstrated that angiogenin has a dual function in cancer progression: it mediates tumor angiogenesis and is also directly involved in cancer cell proliferation. Currently, we are investigating anticancer activity of neamine, a nontoxic analog of neomycin, that blocks nuclear translocation of angiogenin in both endothelial and cancer cells.
More recently, we are studying the role of angiogenin in ALS. Heterozygous mutations in the coding region of angiogenin have been recently reported. We have, for the first time, shown these are loss-of-function mutations. We have also shown strong angiogenin expression in human fetal and adult spinal cord neurons and endothelial cells, confirming the plausibility of angiogenin dysfunction being relevant to the pathogenesis of ALS. Strikingly, systemic administration of angiogenin protein dramatically improves motor muscular function of symptomatic SOD1G93A mice and significantly prolongs their survival. This work has set the foundation for our continuing study on the function of angiogenin in neurodegenerative diseases

Research Expertise 

Dr. Hu’s laboratory has been studying the biological function of angiogenin, a 14 kDa secreted ribonuclease, for many years. This research has uncovered several features of angiogenin biology, including: nuclear translocation in cancer cells, DNA binding to the rRNA promoter, a potent angiogenesis-stimulating activity, and promotion of cancer cell proliferation. The lab’s studies, linking angiogenin to tumor growth, have been the subject of several high-profile articles, that demonstrated the following:

1. Angiogenin directly promotes cancer cell growth.
2. Translocation of angiogenin to the nucleus and its ability to stimulate rRNA transcription correlate with cancer cell growth.
3. Blockage of angiogenin translocation to the nucleus by the antibiotic neomycin or its nontoxic derivative neamine, or curbing of angiogenin expression by RNA interference, leads to a repression of tumor cell growth.
4. Angiogenin plays an important role in endothelial cell growth and angiogenesis.

The data are particularly compelling with respect to prostate cancer, which displays significantly elevated angiogenin expression relative to normal prostate tissue.

Recent work has also revealed an intriguing link between angiogenin and the debilitating and fatal neurodegenerative disease ALS.


Research Interests

Determine if angiogenin confers a protective function for neurons, and if loss-of-function angiogenin mutations are sufficient to trigger the onset of ALS.

Investigate the activity of ODC antizyme in DNA repair and tumor suppression.

Study the possible intersection of angiogenin and growth factors in stimulating angiogenesis and cancer progression.

Further dissect angiogenin’s nuclear localization as a target for drug therapy.

Investigate the in vivo consequences of angiogenin loss-of-function mutations and their role in neurodegenerative diseases, for the purpose of developing more authentic mouse models of diseases, such as ALS. The current “gold” standard for an ALS mouse model involves superoxide dismutase gain-of-function mutations, but experimental therapies that appear effective in this mouse model have not demonstrated efficacy in humans.

Study the tumor suppressor function of ODC antizyme in mouse models to gain insights into its mechanism of action.  


  Posted on: Tuesday, August 25, 2009 - 02:32 PM; by: ming

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