| Program Leader: A. Matouschek, PhD |
|
Program Co-Leader: H. Kiyokawa, MD, PhD |
|
|
The Cancer Cell Biology program of the Robert H. Lurie Comprehensive Cancer Center focuses on basic research in cell biology. This Program was established because of the significant increase in strength in this research area at Northwestern University through hiring and growth of existing faculty. Andreas Matouschek, PhD, and Hiroaki Kiyokawa, MD, PhD, lead the program and are located on the Evanston and Chicago campus respectively. The leadership team was selected to complement each other with respect to their scientific and medical backgrounds and to fully integrate the program over both of Northwestern's campuses. The goal of this program is to increase the amount and quality of the cancer research in cell biology at Northwestern by supporting existing research efforts in this area and by attracting high quality basic researchers to focus their research to a cancer theme. The program consists of 28 faculty from five departments and two schools. Between January 2001 and September 2006 there have been 343 cancer-relevant publications from the current program members. Fifty-Nine (17%) of these publications represent intra-programmatic collaborations and 80 (23%) represent inter-programmatic collaborations. Total current cancer-relevant peer-reviewed funding is $8,231,819 (direct) with $1,863,761 (direct) from NCI and $6,368,058 (direct) from other peer-reviewed sources. The research of program members falls into four broad areas: posttranscriptional regulation of protein function, regulation of subcellular localization of DNA and proteins, the control of cell fate determination, and cancer animal models and therapeutics. These topics play a fundamental role in the control of cell growth and differentiation. Program members study how these mechanisms functional normally and how that function goes awry during neoplastic transformation. An understanding of these mechanisms leads to the development of new technologies to be used in cancer therapy and research.
Back to top
The CCB program has significant strength in cellular regulation at the level of RNA processing. Carthew and Sontheimer elucidated several steps in the biochemical mechanism by which micro RNAs regulate gene expression through their characterization of functional complexes on the RNAi pathway. This pathway is currently attracting significant interest because it is becoming increasingly clear that it is involved in the regulation of many cellular processes. In addition to the fundamental mechanistic studies, Carthew investigates how small RNAs regulate RTK signaling and cell cycle transitions and how they regulate chromatin structure. Uhlenbeck is a distinguished senior biochemist analyzing the fundamental properties of RNA biochemistry with a major focus on the molecular recognition events during translation. Carthew and Sontheimer are also developing RNAi technology for applications in research and therapy.
After translation, most proteins fold into well-defined three-dimensional structures and then function for different times inside and outside the cell. Chaperones assist many proteins in folding transition and gross conformational changes after synthesis and some biochemical processes. Damaged or misfolded proteins are removed from the cell by ATP-dependent proteases. Morimoto and Matouschek investigate the biochemistry and molecular biology of these two classes of catalysts involved in maintaining cellular protein homeostasis. Neoplastic transformation leads to an upregulation of the chaperone response and inhibition of this response sensitizes cancerous cells. Morimoto is also developing drugs that interfere with the chaperone response and, in collaboration investigates how these drugs affect transformed cells. ATP-dependent proteases play a central role in cellular regulation by controlling the concentrations of hundreds of regulatory proteins. The most important of these proteases in eukaryotic cells is the proteasome. Proteins are targeted to the proteasome through post-translational modification with ubiquitin. Matouschek investigates how the proteasome recognizes, unfolds and degrades its substrates. The work on these protein machines has provided insights into cellular regulation, for example by discovering a novel signal for protein processing by the proteasome. Another widespread posttranslational modification is protein phosphorylation by kinases. Weiss investigates how kinase signaling pathways regulate cell morphology by coordinating cytoskeleton organization, membrane trafficking and gene expression. Changes in cell shape are an important hallmark of cancer progression. Weiss's work provides the basis for investigations of these changes and may identify novel therapeutic targets. Lomasney studies the mechanisms of phosphoinositide-mediated signaling and its perturbation in human cancer. Phosphoinositide metabolism is a critical signaling step upstream of a number of cancer-associated protein kinase pathways, including protein kinase-C, and one of important therapeutic targets against cancer.
Back to top
After synthesis, proteins are sorted to different cellular locations and the localization controls protein function. Folsch is investigating how proteins are sorted between the basolateral and apical membranes in epithelial cells. This process is responsible for the organization of these cells and loss of cell polarity is a key event in the transformation of epithelial cells. Hicke is investigating how proteins are removed from the cell surface by endocytosis. Her laboratory is focusing specifically on how ubiquitin modification of receptors and adapter proteins contributes to the molecular mechanism of membrane flow. This process plays a critical role in regulation of signaling processes, including those that control cell growth and differentiation and therefore affect oncogenesis. As an example, the proto-oncogene Cbl is a protein ubiquitin ligase involved regulation of tyrosine kinase signaling.
Soluble proteins are also transported to a different subcellular compartment. Yaseen investigates how proteins are translocated to the nucleus where many, including those studied by Yaseen, are directly responsible for the regulation of gene expression. It is well accepted that the function of proteins is controlled by their subcellular localization. It is much less well understood how the spatial organization of DNA affects its function. Brickner is investigating how the localization of genes within the nucleus affects their expression focusing on the recruitment of genes to the nuclear membrane during their activation. Transcriptional regulation is fundamentally involved in differentiation and oncogenesis. A cellular understanding of this process will likely illuminate how normal regulation is disrupted during oncogenesis and how this process is coupled to the phenomenon of genomic instability.
Back to top
Normal cells have multi-layered mechanisms that govern the cell fate in response to extracellular signals and intracellular conditions. Cell fates determined by this critical process include continued cell cycle progression, differentiation with cessation of proliferation, transient arrest for damage repair (checkpoint), irreversible cell cycle arrest (senescence), and programmed cell death (apoptosis). Perturbation of cell fate determination plays a key role in cancer development. CCB members address this fundamental question from various aspects, as outlined below.
Perturbed cell cycle control is a hallmark of cancer. Since the basic cell cycle machinery, e.g., cyclin-dependent kinases (CDKs), are well conserved among all eukaryotic species, understanding the role of the cell cycle machinery is critical. Recent studies suggest that specific components of the cell cycle machinery are promising targets of chemotherapeutic and chemopreventive strategies. Kiyokawa has been investigating how CDKs and their regulators affect cell fate determination during development and cancer, using mouse models. Especially, he has demonstrated that the cyclin D-dependent kinase CDK4 is dispensable for development but plays an essential role in initiation of breast and skin cancers. His laboratory is currently investigating the mechanism of this action. DNA replication during S phase and mitosis during M phase must be tightly coordinated in order to maintain genomic stability. Cancer cells often exhibit mis-coordination of replication and mitosis. McGarry is studying mechanisms of this cell cycle coordination, using Xenopus laevis as a model system.
Processes that govern the cell fate are critical not only for physiological development but also for cancer development. For instance, resistance to apoptosis is a major characteristic of cancer cells, while overcoming the checkpoint of cellular senescence, or immortalization, is a requisite step of carcinogenesis. Apoptosis and senescence form two major tumor suppressive mechanisms, which represent checkpoint responses to various stress and damages. Ardehali investigates the critical role of mitochondria in apoptosis. To gain novel insights into the mechanisms of apoptotic dysregulation, Cryns is taking an approach to identify and characterize caspase substrates. Gao is investigating transcriptional regulation by BRCA2 protein, the product of a key tumor suppressor gene in breast and ovarian cancers. Dimri is studying how polycomb-family transcription factors control cellular senescence.
Stem cell compartments in various tissues play a key role in tissue homeostasis. Moreover, the concept of "cancer stem cell" is now widely accepted and has significant clinical implications. Eklund and Yaseen work on transcriptional control of hematopoietic stem cells and leukemia's. Kessler investigates mechanisms of coordinated control of the cell cycle and differentiation in neuronal stem cells and progenitor cells. Miller is one of the leaders in the chemokine signaling field and he looks into the role of chemokine signaling in differentiation of glial cells and development of gliomas.
Back to top
Animal models have been essential for cancer research. In particular, genetically engineered mouse models, such as knockout, knockin, and transgenic mice, continue to be powerful tools to dissect complex pathways involved in cancer development and progression. A number of Cancer Cell Biology members utilize mouse and rat models for their research. For example, Eklund studies phenotypes of HOXA10- and ICSBP-knockout mice, which provide critical insights into leukemia development. Kiyokawa has developed and characterized several knockout mouse models with mutations in CDK-regulatory pathways, including Cdk4- and Cdc25A-knockout mice, which are resistant to carcinogenesis. Licht generated Sprouty knockout mice and showed that this protein is critical for WT1 signaling. Reddy has developed and studied several mouse models to study the peroxisome proliferators activated receptors (PPAR)-mediated signaling and liver carcinogenesis. Roy and Wali are experts in the chemoprevention area using rat colon cancer models. Their study using light scattering spectroscopy represents translational studies that take full advantage of novel technology and cancer animal models.
Back to top
|
|
