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During the course of tumor progression, cancer cells acquire a number of characteristic alterations. These include the capacities to proliferate independently of exogenous growth promoting or growth-inhibitory signals, to invade surrounding tissues and metastasize to distant sites, to elicit an angiogenic response, and to evade mechanisms that limit cell proliferation, such as apoptosis and replicative senescence. These properties reflect alterations in the cellular signaling pathways that in normal cells control cell proliferation, motility, and survival. Many of the proteins currently under investigation as possible targets for cancer therapy are signaling proteins that are components of these pathways. Our laboratory is uses chemical biology approaches and models of epithelial tumorigenesis and regulation of keratinocytes proliferation to dissect such pathways.
We have recently identified a novel signaling pathway in keratinocytes involving inhibition of the Notch1 gene downstream of p53, which plays a key role in squamous cell carcinoma (SCC) development. Exploring the downstream effects of activated Notch receptor in the epidermis, we found that the small GTPase RhoE is a new transcriptional target of Notch1, which is essential for the differentiation switch in keratinocytes. RhoE deficiency in vitro and in vivo renders keratinocytes resistant to Notch1-mediated induction of differentiation thereby favoring uncontrolled growth and proliferation. Furthermore, we have strong evidence that RhoE binds to activated Notch1 and mediates the recruitment of the Notch1-transcriptional complex to the promoters of its target genes. Our working hypothesis is that RhoE is a key regulator of Notch1-mediated commitment to differentiation and suppression of carcinogenesis/tumorigenesis in the epidermis. The mechanistic understanding of the pathway(s) controlling the Notch-RhoE signaling cascade in the epidermis is expected to eventually translate into the development of therapeutics for the treatment of skin SCCs and other epithelial malignancies with down-modulated Notch signaling. It also brought to light an unexpected function of RhoE in the cellular response to Endoplasmic Reticulum Stress and thus paved the way for the discovery of novel modulators of these processes.
Our profound interest in Drug Development also complements the long-term goal of the laboratory to dissect specific stress-mediated responses of the cell and to develop unique ways to modify them. Mammalian Y-box binding protein-1 (YB-1) is a member of the DNA/RNA-binding family of proteins with an evolutionarily conserved cold-shock domain (CSD). Both bacterial and mammalian cold-shock domain proteins are ubiquitously expressed and involved in fundamental processes such as DNA repair, mRNA transcription, splicing, translation, and stabilization. Consistent with its essential biological functions, targeted disruption of YB-1 in mice causes severe developmental defects and embryonic lethality. Numerous studies point to a role for YB-1 in malignant transformation, with evidence for oncogenic functions. A pro-oncogenic role for YB-1 is suggested by its higher expression in actively proliferating tissues and multiple human malignancies, as well its ability to activate transcription of proliferation- related genes through binding to the Y-box promoter elements of the latter. We are currently studying the role of YB-1 in normal keratinocyte biology as well as in the pathogenesis of keratinocyte-derived cancers. In addition, we are also developing approaches for small molecule based inhibition of YB-1 expression and activity.
Kristina Todorova, Ph.D.
Eunjeong Kwon, Ph.D.
Anna Mandinova, M.D., Ph.D.
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