Ph.D., National Defense Medical Center (Taiwan)
keratinocyte stem cells, skin carcinogenesis, DSS1, RPN3/S3, ubiquitin-proteasome system, protein degradation, p53
Proteasome regulates cellular proliferation, differentiation, apoptosis and transformation via an orchestrated degradation of cell-cycle regulators, transcription factors, tumor suppressors, oncoproteins and membrane proteins. Proteasome assembly is dynamically controlled and fine-tuned by associating the proteolytic 20S core particle (CP) with an inhibitory (like PI31) or stimulatory complex (e.g., 19S regulatory particle (RP) or PA700, PA28αβ, PA28γ, and PA200). The 26S proteasome comprises two subcomplexes, 19S RP and 20S CP, to form the RP2CP or RP1CP, and plays a pivotal role in controlling the levels of many short-lived proteins through ATP and ubiquitin-dependent protein degradation in the cytoplasm and nucleus of eukaryotic cells. Aberration of the ubiquitin-proteasome system (UPS) has been implicated in the pathogenesis of many human disease states, including cancers, heart diseases, obesity, diabetes, neurodegenerative, inflammatory and aging-related disorders. One of the proteasome specific inhibitors Bortezomib has been currently developed by the Millennium pharmaceutical company and been approved by the US FDA in 2003 and used in clinical to treat the patients with relapse multiple myeloma. This drug can target 20S proteasome core enzymes, which play important roles in many processes that keep cells alive and help them reproduce, by interfering with their proteolytic activity, and causes cancer cells to die and eventually slows down the tumor growth.
We have previously identified a mouse Deleted in Split hand/Split foot gene 1 (DSS1) as a novel TPA-inducible gene with possible involvement in early stage of skin tumorigenesis. DSS1 was originally identified on human chromosome 7q21.3-q22.1 as a gene deleted in patients with the inherited heterogeneous limb developmental disorder called ectrodactyly or split hand/split foot malformation type 1 (SHFM1). SHFM1 affects 1 in 8,000-25,000 individuals in the United States and is an autosomal dominant disease characterized by deep median clefts, missing digits, fusion of digits, and abnormalities of genitourinary and craniofacial structures and the skin. DSS1 has been reportedly functioned as a molecular glue and be involved in many cellular processes, including development, differentiation, DNA repair, homologous recombination, genome stability, cellular proliferation and neoplastic transformation, protein degradation, and mRNA exportation. Notably, baker’s yeast Sem1p, the human DSS1 homolog, was recently found to bind to the lid subcomplex of the proteasome 19S RP and function as a component of the 26S proteasome that can enhance proteasome stability and play a role in ubiquitin-dependent proteolysis. However, the mechanisms by which DSS1 exerts its biological effects through the UPS in cancers are currently unknown. Our laboratory is particularly interested in identifying roles of the proteasome subunits in cancers, more specifically focus on the subunits of 19S RP like DSS1, RPN3/S3, PSMD5/S5b and gankyrin molecules in skin and cervical cancers. My research studies to pursue the observation of these genes are described as follows: (I) A functional role of the Deleted in Split hand/Split foot gene 1 (DSS1) protein in human cervical cancers. (II) Characterization of the proteasome chaperone PSMD5/S5b in human cervical cancers. (III) Conditional knockout of the DSS1 gene in mouse epidermis. (IV) Evaluation of the transcriptional regulation by analyzing the binding sites of transcription factors in DSS1 gene promoter region. (V) Development of the DSS1 promoter/Luc reporter system to screen for compounds that inhibit or activate DSS1 gene expression.
Dr. Yinghao Zhang - Postdoctoral Fellow
Hannah Pridgen - Research Assistant
Jennifer Zambales - Volunteer