Role Of CTCF In Tumor Development

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The Molecular Pathology Section (MPS) lead by Dr. Victor V. Lobanenkov within the Laboratory of Immunopathology (LIP) NIAID was established in September 1999. Dr. V. Lobanenkov received Master Degree in Nuclear Physics from the Institute of Physics and Engineering in 1977, switched to cancer biology as a second field of study, and received his Ph.D. degree in experimental oncology from the Cancer Research Center in Moscow in 1981. Following his work at the Royal Cancer Hospital in London, he was appointed as a Head of Molecular Carcinogenesis group at the Institute of Carcinogenesis: All-Union Cancer Center of the former USSR and a Visiting Scholar at the Institute of Cancer Research, Royal Cancer Hospital of London. In 1990, he was invited to work at the Fred Hutchinson Cancer Research Center in Seattle, WA where he held a position of the Foreign Faculty in Residence with an independent research agenda funded by NIH/NCI RO1 grants until moving to NIH in 1999. Most of the research projects carried out in LIP MPS are focused on structure and function of CTCF gene that was identified and cloned by V. Lobanenkov and co-workers in 1990, and was initially characterized as an evolutionarily conserved negative transcriptional regulator of vertebrate MYC oncogenes. CTCF contains 11 Zn finger (ZF) DNA-binding domain conserved from Drosophila to frogs to birds to mice to men. Different CTCF-target sites (CTSs), recognized by different combinations of CTCF ZFs, perform distinct regulatory functions. Depending on the context, different CTSs play distinct roles in transcriptional regulation by CTCF including promoter repression, activation, and creation of the thyroid hormone-responsive silencers. These studies resulted in more then 30 publications, and the USA and foreign Patents issued in 1999. The very first review on CTCF published in "Trends in Genetics" in 2001 by V. Lobanenkov and his major collaborators from Germany and Sweden, provides a summary of experimental results which together show that CTCF is a uniquely versatile transcriptional regulator with diverse functions linked to epigenetics and disease. It is an exceptionally evolutionarily conserved Zinc Finger (ZF) phosphoprotein that binds via combinatorial utilization of the eleven ZFs to ~ 50 bp long DNA target sites with remarkable sequence variation. Formation of different CTCF-DNA complexes, a subset of which is CpG-methylation-sensitive, results in distinct functions including gene activation, repression, silencing or chromatin insulation. Disrupting the spectrum of target specificities by ZF mutations or by abnormal selective methylation of certain CTCF-targets is associated with cancer. CTCF emerged, therefore, as a central player in networks linking expression domains with epigenetics and cell growth regulatory processes. It is thus not surprising that in recent years there has been a rapidly growing interest in the CTCF gene. Besides LIP NIAID, different aspects of CTCF biology have become a major focus of research in several other laboratories both within and outside NIH, and abroad. In 2000-01, MPS LIP continued to work on a program directed to better understanding of CTCF normal function in development, cell-cycle regulation, and gene imprinting; and of CTCF malfunction in cancer, and in other human diseases associated with abnormal site-specific DNA methylation (for instance, in congenital myotonic dystrophy). This program takes advantage of cancer-prone mouse CTCF knock-out models, and of Drosophila genetics based on identification and cloning of the CTCF homologue in flies. Several new publications, including those in "Cancer Research" and in "Nature Genetics", came out in 2001, while several more are being submitted. Identification and functional characterization of cancer-associated CTCF mutations can be viewed as experiments of Nature that reveal critically important CTCF target genes and protein partners that are involved in regulation of CTCF function. Identifying such genes and partners reveals regulatory gene networks and pathways which define tumor phenotype(s), and thus leads the Molecular Pathology Section well beyond studies of CTCF per se because novel genes in a pathway of mutant CTCF are to be, in turn, potential oncogenes or tumor suppressor genes. By September 2001, some of these proprietary genes have already been characterized and are now being patented by NIAID NIH, and evaluated for diagnostic and therapeutic purposes. Several other genes encoding CTCF-interacting proteins are at the initial stages of deciphering their role(s).