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.
Directions to Charlestown Navy Yard MGH East - Building 149
From Storrow Drive
From 93 North
- From the end of Storrow Drive (Leverett Circle) keep to the far right and take a sharp right (do not go up the ramp), and continue beneath the underpass one quarter mile to the light.
- Turn left onto Causeway street under the elevated subway tracks. The Fleet Center will be on your left, the North Station T station on your right.
- One block past the Garden, turn left on to N. Washington Street, passing over the Charlestown Bridge.
- At the first light after the bridge, take a right. Go through three traffic control lights.
- At the fourth light, turn right into Navy Yard (Gate 5 - 13th Street). To park, take first left onto Fifth Avenue. Building 149 is one block on the right.
- The parking garage entrance is on the right about half way down the block.
From 93 South
- Take the Mass Pike (I-90) to I-93 North (Exit 24B)
- Take the Storrow Drive Exit (Exit 26)Stay in the left lane once getting on the exit ramp. Follow signs for North Station/Leverett Circle Go through 1 light and take left at the 2nd light (almost immediately after the first)
- Get immediately into the right lane
- Take a right at the light onto Route 28N
- The Museum of Science will be on your left
- Take a right at the 3rd light (there is a sign at the corner for Charlestown)
- Go over the bridge and get in the right lane (City Square)
- Take your 1st right and get into the left lane
- Turn left at the 2nd light (immediately before Charlestown Bridge, at City Square) onto Chelsea Street (If you go over bridge, you've gone too far).
- Go through three traffic control lights
- At the 4th light, turn right into the Navy Yard (Gate 5 - 13th Street).
- To park, take first left onto Fifth Avenue. Parking Garage entrance is on the right above half way down the block. Building 149 is one block on the right once you turn into Gate 5. Building 149 is also connected to the parking garage.
- Take Exit 28 (Charlestown/Sullivan Square).
- At the end of the exit where the read forks stay to the right and proceed past the bus terminal to the rotary at Sullivan Square.
- Go halfway around the rotary towards Charlestown (the Schrafts building with a large American flag on top of it will be on your left).
- Cross the railroad tracks and take a left at the fire station onto Medford Street.
- At the end of Medford street turn left onto Chelsea Street and make an immediate right into the Navy Yard.
- The MGH East Research Building (Bldg. 149) will be on the right and is connected to the parking garage by overhead walkways.
By Public Transportation & the MGH/Partners Shuttle
- Direct the driver to the MGH East, Building 149 in the Charlestown Navy Yard.
- The CBRC is on the 3rd Floor of Building 149.
- Take the T (Green Line) to North Station
- Take the MGH/Partners Shuttle bus to the Charlestown Navy Yard MGH East Research Building (Building 149).
- The CBRC is on the 3rd Floor.
- The MGH/Partners Shuttle bus leaves MGH on Blossom Street and stops at North Station on Canal Street by the Green Line T stop. The shuttle goes every 15 minutes during working hours. (Less often on the weekends and holidays).
- To get to the CBRC, take the first set of elevators to the left of the main entrance by the Security Desk to the third floor. You may need to check in with security on the main level of Building 149.
- From the elevator, exit to the East to the CBRC offices, or in the opposite direction for the laboratories.