National Taiwan University (M.D.), Baylor College of Medicine (Ph.D.)
Columbia University College of Physicians & Surgeons (Post-Doct.)
Molecular mechanism of c-Myc and NBS1 overexpression mediated downstream signal transduction and their roles in lung cancer and head and neck cancer
c-MYC proto-oncogene is involved in the control of cell cycle progression, proliferation, metabolism, and apoptosis. c-MYC protein is a transcription factor which functions via heterodimerization with MAX, a related protein which, like c-MYC, contains basic (b), helix-loop-helix (HLH) and leucine zipper (LZ) domains, but lacks the transactivation domain present in the amino-terminus of c-MYC. MYC-MAX complexes stimulate transcription of target genes containing the MYC-MAX binding site (E-box). The expression of c-MYC protein is tightly controlled during cell proliferation and differentiation. c-MYC is one of the most frequently altered genes in human cancer. Transgenic mice with c-MYC overexpression caused tumor formation. All these results demonstrated the central role of c-MYC in cell growth, proliferation, and transformation. Elucidation of the molecular mechanisms will require identification of important downstream pathways regulated by c-MYC.
We have characterized several c-MYC downstream target genes including iron metabolism (H-ferritin and IRP2), telomerase reverse transcriptase gene-TERT, and cAMP pathway (protein kinase A catalytic subunit beta) during the past eight years. Recent results included the identification and characterizations of two c-MYC downstream target genes, NBS1 and HSP90A. HSP90A is directly activated by c-MYC, linking the modulation of multiple signal transduction pathways by HSP90A to c-MYC activity.
NBS1 is a protein involved in DNA double-strand break (DSB) repair. We demonstrated that NBS1 is a direct c-MYC target gene. This result links the function of c-MYC to the regulation of DNA DSB repair pathway operating during DNA replication. In addition, we demonstrated that NBS1 overexpression induces transformation through the activation of PI 3-kinase/Akt. Increased NBS1 expression is a significant prognostic marker in head and neck cancer. Our recent results showed that NBS1 overexpression induces epithelial-mesenchymal transition (EMT) through the upregulation of Snail and co-expression of NBS1 and Snail predicts metastasis of HNSCC patients.
Future directions include several aspects: 1) further characterization of novel c-MYC target genes, 2) characterization of the molecular mechanisms of NBS1 overexpression induced transformation and metastasis; 3) search for downstream target genes of Snail and their functional characterizations; 4) search for pathways regulated by NBS1 overexpression using cDNA microarry and proteomics approaches. These approaches will delineate the molecular mechanism of c-MYC and NBS1 overexpression mediated downstream signal transduction pathways and their roles in the tumorigenesis of lung cancer and head and neck cancer.
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