Research Interests:
The major interest of
our laboratory is to investigate the biological responses of environmental
stress. The action of heavy metals on the cellular metabolism, signal transduction
and transcriptional regulation are focused. We are currently investigating
the regulation of metallothionein (MT) gene expression under various stresses.
MT is a low molecular weight, cysteine-rich, metal-binding protein that is
synthesized to protect cells against heavy metal toxicity. Upon metal stimulation,
the transcriptional factor of MT gene, metal responsive transcription factor
1 (MTF-1), translocates from cytoplasm to nucleus and binds to metal responsive
element (MRE) at the promoter region to initiate the transcription of MT gene.
We found that MTF-1 is subjected to various post-translational modifications
which may leads to a functional alternation of the transcriptional factor.
We are investigating the molecular mechanism and factors involved in the modifications
to elucidate the physiological roles of the modifications. MTF-1 is an essential
protein that is required for embryonic development of mammals. Our research
may reveal the fine regulatory mechanisms of genes modulated by MTF-1.
Besides the transcriptional regulation of MT gene, we also investigated the
mechanism for cadmium-induced necrosis. The target site for a necrosis inhibitor
was also analyzed. Taking advantage of the reversible metal-binding characteristics
of MT, we were able to develop protein chips to quantify bioavailable metal
contents in the aquatic phase. Additionally, nano-sized germanium particles
were fabricated to serve as a radiosensitizer. Modifications of the particles
are conducted for biomedical applications.
實驗室研究的重點在於探討細胞遭受重金屬逆境時，在分子及細胞層次上所產生的效應。尤其是金屬硫蛋白(metallothionein,
MT)基因的轉錄調控機制及控制其基因啟動之轉錄因子(MTF-1)的轉譯後修飾作用對其轉錄功能的影響。MTF-1平時位於細胞質中，當受金屬刺激後，即會進入細胞核中，辨識特定DNA序列，以啟動基因的轉錄作用。我們發現MTF-1上有若干轉譯後修飾作用會顯著的影響其轉錄功能，其改善可能影響到細胞的對抗重金屬毒害、氧化逆境、甚而死亡及致癌性等作用。目前，我們對這些後修飾作用的時機、細胞位置、牽涉到的酵素及訊號傳遞系統等進行系列性的研究。除了轉錄調控的研究外，我們也探討重金屬對細胞傷害的機制。尤其是造成細胞壞死(necroptosis)的作用，及抑制該作用產生的藥物之作用方式。我們也發展出生物晶片，利用MT結合金屬的特性，製造出金屬感應晶片，以分析液體中，生物有效之金屬濃度。同時也利用金屬奈米粒子作為輻射敏感物質，進行生醫相關的研究。