Leslie I. Gold, PhD Research Summary


Leslie I. Gold, PhD

Cancer Biology:

The laboratory studies loss of growth regulation in cancer, particularly hormone-regulated cancers.  Specific objectives emphasize alterations in cancer cells with respect to the regulation of cell cycle proteins by ubiquitin-mediated degradation, nuclear-cytoplasmic shuttling of cell cycle proteins, growth factor signaling pathways, particularly TGF-β, hormone-regulated growth, and stromal/epithelial interactions.  For example, we are the first to show that TGF-β, estrogen, and progesterone control endometrial epithelial cell proliferation by regulating the protein levels of the cyclin-dependent kinase inhibitor, p27kip1 (p27) through the ubiquitin pathway (Diagram).  Therefore, identifying specific inhibitors of the E3 ligase, Skp2 to potentially prevent p27 degradation to regain growth control is a potential specific therapy for endometrial carcinoma and other human cancers showing loss of nuclear p27.  We utilize epithelial and stromal cells, isolated from normal and malignant endometrium, in primary cultures, co-cultures, and 3-dimensional matrices as our major model systems.  These physiological paradigms afford optimal approaches to understanding the role of stromal cells surrounding malignant glands in malignant progression (tumor microenvironment) and a greater probability for defining molecular targets for translation into novel treatments for cancer prevention and therapy.

Wound Healing:

We discovered that the intracellular calcium-binding endoplasmic reticulum (ER) chaperone protein, calreticulin has non-ER functions of topically enhancing the rate and quality of wound healing and exogenously, inducing proliferation, migration, and matrix protein induction of cells involved in the wound healing process.  The mechanisms involved in how calreticulin induces these functions from the outside-inward and the receptors are unknown opening a new area for the lab to explore.

Research Interests:

Translational medicine, hormonal carcinogenesis, normal and malignant growth regulatory mechanisms, post-translational protein modifications, cell cycle, ubiquitin pathway regulation of growth, TGF-β signaling, stromal/epithelial interactions and cell substrate interactions in cancer progression, molecular targets for cancer prevention and therapy, wound/tissue repair, developing physiological model systems.

Research Key Words:

Cancer biology and prevention, growth regulation, cell cycle, ubiquitin-proteasome pathway, gonadal steroid action, TGF-β signaling, wound healing, calreticulin, proteomics.

Honors:

Permanent member of Metabolic Pathology and Tumor Cell Biology IRGs, NIH; Council, American Association Cancer Research (WICR), SEP Review Panel for Gynecological SPORE, NIH; Review Panel for AACR Fellowships,  Ad hoc Reviewer for numerous IRGs, NIH; Associate Editor, Molecular Signaling.

Diagram of Leslie Gold research

[Click on image to enlarge] 

The diagram depicts the growth regulatory action of TGF-β, progesterone and estrogen on the degradation of cell cycle proteins via the ubiquitin proteasome system (UPS).   TGF-β and progesterone block cells in G1by preventing p27 degradation by the ubiquitin  E3 ligase complex, SCF-Cks1/Skp2.  This is achieved by increasing the E3-ligase APC-Cdh1, which degrades SCF-Cks1/Skp2.  Estrogen increases progression to S phase by degrading p27 via an increase in SCF-Cks1/Skp2.  Starting from G1: The phosphatase, Cdc14 removes phosphates from Cdh1 to induce binding to  APC.  The APC-Cdh1 complex is an E3 ligase that ubiquitylates SCF-Skp2 for proteasomal degradation thereby leaving p27 intact to block cells in G1.  Cdk1 phosphorylates Cdh1 causing its degradation by the proteasome.  This causes Cdc20 to bind to APC leaving the SCF-Cks1-Skp2 E3 ligase active to degrade p27 for cell cycle progression through S phase.   APC bound to Cdc20 ensures progression through G2 to M phase. We show that p27 is an important molecular target for endometrial carcinoma as well as many other human cancers in which p27 is constantly degraded to allow cell proliferation.   As general proteasome inhibitors affect degradation of many proteins involved in many physiological and pathological processes, we are exploring specific inhibitors of Skp2 E3 ligase activity to preserve nuclear p27 and regain cell cycle arrest for cancer prevention and therapy.