462 First Avenue
New York, NY 10016
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.
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.
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.
TGF-beta activates APC through Cdh1 binding for Cks1 and Skp2 proteasomal destruction stabilizing p27kip1 for normal endometrial growth
Pavlides, Savvas C; Lecanda, Jon; Daubriac, Julien; Pandya, Unnati M; Gama, Patricia; Blank, Stephanie; Mittal, Khusbakhat; Shukla, Pratibha; Gold, Leslie I. TGF-beta activates APC through Cdh1 binding for Cks1 and Skp2 proteasomal destruction stabilizing p27kip1 for normal endometrial growth. Cell cycle. 2016 Apr 2;15(7):931-947 (2024442)
High-level secretion of native recombinant human calreticulin in yeast
Ciplys, Evaldas; Zitkus, Eimantas; Gold, Leslie I; Daubriac, Julien; Pavlides, Savvas C; Hojrup, Peter; Houen, Gunnar; Wang, Wen-An; Michalak, Marek; Slibinskas, Rimantas. High-level secretion of native recombinant human calreticulin in yeast. Microbial cell factories. 2015 Oct 15;14(1):165-165 (1803742)
Inhibitors of Skp2 E3 ligase-mediated degradation of p27kip1 as a novel therapeutic approach to malignant pleural mesothelioma
Daubriac, Julien; Melamed, Jonathan; Pandya, Unnati; Pass, Harvey I; Gold, Leslie I. Inhibitors of Skp2 E3 ligase-mediated degradation of p27kip1 as a novel therapeutic approach to malignant pleural mesothelioma [Meeting Abstract]. Cancer research. 2015 AUG 1;75:?-? (2064372)
Unfolding the complexities of ER chaperones in health and disease: report on the 11th international calreticulin workshop
Gold, Leslie; Williams, David; Groenendyk, Jody; Michalak, Marek; Eggleton, Paul. Unfolding the complexities of ER chaperones in health and disease: report on the 11th international calreticulin workshop. Cell stress chaperones. 2015 Sep 22;20(6):875-883 (1812692)
A new role for the multifunctionalwound healing agent calreticulin (CRT) in combating infection: Significance for treating diabetic foot ulcers
Gold, L I; Pavlides, S C; Ojeda, J; Eaton, B; Panchal, R G. A new role for the multifunctionalwound healing agent calreticulin (CRT) in combating infection: Significance for treating diabetic foot ulcers [Meeting Abstract]. Wound repair & regeneration. 2014 March- April;22(2):A42-A42 (1361312)