Myung Hee Park, Ph.D.
Oral and Pharyngeal Cancer Branch
Building 30, Room 211
30 Convent Drive
Bethesda, MD 20892
We have been interested in four related topics:
- the role of polyamines in cellular regulation
- characterization of the hypusine modification pathway in eIF5A
- the mechanism of eIF5A action in protein synthesis
- the role of eIF5A isoforms in cell proliferation, animal development and tumorigenesis
- The polyamines (putrescine, spermidine and spermine) are ubiquitous polycations in living organisms and are absolutely required for growth and development in the eukaryotic kingdom. They have been implicated in diverse biological regulation at the levels of transcription, translation, posttranslational processing and modification, ion channel gating, and membrane stability. Polyamine levels within cells control cell proliferation, differentiation , apoptosis and transformation. Although the precise molecular mechanisms of polyamine regulation have been elucidated in a few specific cases, their major function in global cell physiology is still poorly understood. We are studying polyamine function by transfection of the polyamine metabolic enzyme spermidine/spermine acetyltransferase 1 (SSAT1) in mammalian cells. Overexpression of this enzyme results in almost complete depletion of cellular polyamines. When SSAT1 is cotransfected with a reporter gene GFP, GFP expression is totally blocked. We are investigating the mechanism underlying the inhibition of the expression of the reporter gene in polyamine-depleted cells.
- One specific function of a cellular polyamine is defined by the requirement for spermidine for the activation of eukaryotic translation initiation factor 5A (eIF5A) through its posttranslational modification. We discovered this pathway and established the mechanism of hypusine synthesis in eIF5A and the essential role of the hypusine/deoxyhypusine modification in the activity of eIF5A and in eukaryotic cell proliferation. The biosynthesis of hypusine occurs in two enzymatic steps. In the first step, deoxyhypusine synthase catalyzes the transfer of the 4-aminobutyl moiety of spermidine to a specific lysine residue of the eIF5A precursor to form a deoxyhypusine residue. This intermediate is hydroxylated by deoxyhypusine hydroxylase to complete hypusine synthesis and eIF5A activation. Potent inhibitors of the first step enzyme, deoxyhypusine synthase, have been developed and shown to exert strong antiproliferative effects in mammalian cells including human cancer cells. We are investigating the structure and mechanism of deoxyhypusine hydroxylase to develop specific inhibitors as potential therapeutic agents against cancer and HIV1 infection.
- Although eIF5A stimulates the first peptide bond formation in an in vitro methionyl-puromycin synthesis assay, its precise mode of action and its physiological function are not fully understood. Recent polysome analyses data in yeast and mammalian cells suggest a role for eIF5A in the elongation step of translation. eIF5A binding to ribosome was reported to be dependent on the hypusine modification. The characterization of eIF5A binding to the ribosome will provide new insights into the mode of its action. We constructed a polycistronic vector to co-overexpress eIF5A, deoxyhypusine synthase and deoxyhypusine hydroxylase in E. coli and purified large quantities of highly pure recombinant eIF5A proteins containing either hypusine, deoxyhypusine or lysine to carry out structure/function studies and ribosome binding studies.
- eIF5A exists in two closely related isoforms in mammals. Both isoforms have been implicated in certain human neoplasia/cancers as a diagnostic or a prognostic marker. Although eIF5A-1 levels are often enhanced in rapidly proliferating tissues such as cancer, it is constitutively expressed in all cells and tissues. On the contrary, eIF5A-2 is expressed in a tissue-specific manner in brain and testis and is not detected in other normal tissues, suggesting a differentiated function for this isoform. eIF5A-2 expression is enhanced in various human cancer tissues and cells and this isoform has been proposed as an oncogene. In order to determine the role of eIF5A in animal development, we have generated heterozygous knockout mice lacking eIF5A-1 or deoxyhypusine synthase gene. The Eif5a-1-/- or Dhps-/- homozygous knockout leads to early embryonic lethality on the stage of E6.5, indicating their vital role in early embryonic development. We have also generated transgenic mice expressing human eIF5A-1 or eIF5A-2 to determine whether overexpression of either isoform alters the sensitivity of mice to chemically induced carcinogenesis in animal tumor models.
Myung Hee Park has been chief of the Molecular and Cellular Biochemistry Section, Oral and Pharyngeal Cancer Branch since 1998. She leads a research group exploring the role of polyamines and a polyamine-modified cellular protein, eukaryotic translation initiation factor 5A (eIF5A) in eukaryotic protein synthesis, cell proliferation and tumorigenesis. She has discovered a new cellular pathway in which one cellular protein, the eIF5A precursor, is modified by the polyamine spermidine to convert its specific lysine residue to a unique amino acid, hypusine, and demonstrated that hypusine modification is required for the activity of eIF5A in protein synthesis and cell proliferation. Her group further established the enzymatic steps of hypusine synthesis and cloned, purified and characterized the mechanism and structural properties of the two enzymes, deoxyhypusine synthase and deoxyhypusine hydroxylase. They developed potent inhibitors of the enzymes for their potential application in the treatment of various diseases, including cancer, diabetes and HIV1 infection, in which eIF5A has been implicated.
Dr. Park received her Ph.D in chemistry from Brown University in 1976. She did her postdoctoral work at the Massachusetts Institute of Technology (1976-1978). In 1979, she joined NIDCR and initiated her research on hypusine, eIF5A and polyamines.
She is recognized for her pioneering research on the hypusine modification of eIF5A and studies on the functions of polyamines and eIF5A as key regulators in eukaryotic cells. She has published her original studies in prestigious journals and has been invited to speak at many national and international meetings.
Joe YA, Wolff EC, Lee YB, Park MH. Enzyme-substrate intermediate at a specific lysine residue is required for deoxyhypusine synthesis. The role of Lys329 in human deoxyhypusine synthase. J Biol Chem. 1997;272(51):32679-85.
Park JH, Aravind L, Wolff EC, Kaevel J, Kim YS, Park MH. Molecular cloning, expression, and structural prediction of deoxyhypusine hydroxylase: a HEAT-repeat-containing metalloenzyme. Proc Natl Acad Sci U S A. 2006;103(1):51-6.
Mandal S, Mandal A, Park MH. Depletion of the polyamines spermidine and spermine by overexpression of spermidine/spermine N¹-acetyltransferase 1 (SAT1) leads to mitochondria-mediated apoptosis in mammalian cells. Biochem J. 2015;468(3):435-47.
Mandal S, Mandal A, Johansson HE, Orjalo AV, Park MH. Depletion of cellular polyamines, spermidine and spermine, causes a total arrest in translation and growth in mammalian cells. Proc Natl Acad Sci U S A. 2013;110(6):2169-74.
Mandal A, Mandal S, Park MH. Genome-wide analyses and functional classification of proline repeat-rich proteins: potential role of eIF5A in eukaryotic evolution. PLoS One. 2014;9(11):e111800.
Related Scientific Focus Areas
Molecular Biology and Biochemistry
This page was last updated on May 18th, 2012