Autobiography of Xiaodong Wang
Born in Wuhan, China, I was raised by my grandparents from the age of two when my mother became seriously ill. I spent my childhood in Xingxiang, Henan Province with my grandfather, Jingshang Wang, who was an English teacher in high school, and my grandmother, Wanru Xi, who took early retirement from her primary school teaching job to take care of me full time.
When I entered elementary school in 1969, it was the third year into The Cultural Revolution. There was not much academic learning. Not until 1977, when regular school education resumed and the door to higher education reopened, did I start studying. In 1978, I was able to enter one of the top high schools in the Province, the High School Affiliated to Henan Normal University.
I started my college education at Beijing Normal University in the fall of 1980. Dr Shaobai Xue, a professor in cell biology, supervised my undergraduate thesis research and introduced me to modern cell biology and biochemistry. His belief in using biochemistry methods to solve biological problems influenced me to continue my graduate study in this field.
I came to the US through a State-sponsored program organized by Professor Ray Wu from Connell University - the Chinese-United States Biochemistry Examination and Application (CUSBEA) - which provided a major bridge to enter US graduate schools. In the hot summer of 1985, I arrived at the University of Texas Southwestern Medical Center in Dallas to begin my postgraduate training. I joined Dr. Richard Padgett's laboratory to study mRNA splicing. This period greatly advanced my understanding in biochemistry and molecular biology. In particular, the in-depth training in protein and nuclear acid chemistry set me up well for my future research. It is also during this period that I married Xiaying Zhu and started a family.
I joined Drs Brown and Goldstein as a postdoctoral fellow in 1991 to study the molecular mechanism for feedback regulation of cholesterol homeostasis in cells. After two years, my studies there led to the discovery that cells regulate their cellular cholesterol content by cholesterol-regulated cleavage of SREBP, a transcriptional factor that makes mRNA from genes encoding proteins for cholesterol import and synthesis.
In the next two years at Brown and Goldstein's laboratory, I focused on searching for the protease that cleaved SREBP. I did not find the cholesterol regulated protease but unintentionally identified caspase-3, a member of a protease family responsible for executing apoptosis, a programmed form of cell death.
After moving to the Department of Biochemistry at Emory University in Atlanta, Georgia in May 1995, I started to study caspase-3 activation during apoptosis in my own laboratory. Caspase-3 usually stays dormant in living cells and only becomes activated during apoptosis.
Using classical biochemical fractionation and reconstitution methods, we identified three components that were necessary and sufficient in activating caspase-3. The first required component turned out to be cytochrome c, a well-known component of mitochondria electronic transfer chain. We discovered that cytochrome c release from mitochondria was a critical regulatory step during apoptosis, a step controlled by the Bcl-2 family of proteins. Another component is Apaf-1 for Apoptotic Protease Activating Factor-1; and the third componet was procaspase-9. When released from mitochondria to cytosol, cytochrome c binds to Apaf-1 leading to the formation of a protein complex that is capable of recruiting and activating procaspase-9. Caspase-9 in turn cleaved procaspase-3 to activate it.
In August 1996 I moved back to UT-Southwestern to join Dr Steve McKnight, the new Chair in the Biochemistry Department. A year later, I was also appointed as an assistant investigator to the Howard Hughes Medical Institute.
In 2000, we identified another mitochondrial protein Smac, which functions in apoptosis by removing the inhibition of caspases imposed by IAP (Inhibitor of apoptosis proteins). Smac antagonizes IAPs function by binding to them with its N-terminal 4 amino acid residues. Currently, there are several biotech and pharmaceutical companies trying to develop small molecule mimetics of these four amino acids. It can potentially be used for the treatment of cancer, in which IAP proteins are highly expressed to give cancer cell survival advantage.
We would like to continue our biochemical studies of apoptosis in future focusing on how to specifically induce apoptosis in cancer cells with chemical compounds such as Smac mimetic while leaving most of the normal cells intact.
12 September 2006, Hong Kong