Russian scientist Anna Prokhorchuck working with UK and US scientists has found that mice lacking a protein called Kaiso show resistance to intestinal cancer. Kaiso, which this study showed is upregulated in intestinal tumors in mice and is expressed in human colon cancers, seems to play “an essential role in mammalian synapse-specific transcription.” they say in a study published this month in Molecular and Cellular Biology.

Mice bred to lack the Kaiso protein were healthy and fertile, with no detectable abnormalities of development or gene expression. “However, when crossed with mice bred to develop intestinal tumors, Kaiso-null mice showed a delayed onset of intestinal tumorigenesis,” the researchers say. “Our data suggest that Kaiso plays a role in intestinal cancer and may therefore represent a potential target for therapeutic intervention.”

Sscientists in Canada, who categorize Kaiso as “a new member of the POZ-zinc finger family of transcription factors implicated in development and cancer,” are at work with US scientists at Vanderbilt, Tenn. to develop monoclonal antibodies to block Kaison action.

“BTB/POZ (Broad Complex, Tramtrak, Bric à brac/pox virus and zinc finger) family of zinc finger transcription factors.” or POZ-ZF proteins for short, are “strongly implicated in development and cancer,” the Canadians say.

The Scottish-Russian team describe Kaiso as a “BTB domain protein that associates with the signaling molecule p120-catenin and binds to the methylated sequence mCGmCG or the nonmethylated sequence CTGCNA to modulate transcription.”

Approaches to use this information to develop anti-cancer drugs is now being developed also in Russia by Anna Prokhorchuk and scientists at the Bioengineering Centre, Russian Academy of Sciences, jointly with American colleagues sponsored by the international CRDF foundation and the Federal Agency for Science and Innovation (Rosnauka).

Any cancerous disease changes the genetic landscape – some genes are suppressed, others get activated, which results in tumour growth, the formation of metastases, and cancer spreads beyond immune system control. The universal mechanism which regulates genes’ activity is DNA methylation, where a methyl group is joined to a certain section of a molecule. Special methyl-DNA binding proteins come into action, bound with a section of the methylated DNA and this suppresses gene activity. The researchers are interested in one of such proteins named Kaiso. They assume that this protein plays an important role in the intestine cancer development, and it can be used for diagnostics and treatment.

First, the researchers measured the level of expression of the Kaiso protein gene in intestinal tumours in mice and in human patients. The level of expression turned out to be dozens of times higher than that in healthy organs and tissues. ‘Kaiso-zero’ mice were then used which were found to be resistant to cancer. The same resistance to cancer was acquired by mice whose DNA methylation had been suppressed by other methods.

As the Kaiso protein content in the majority of human tumours is much higher than that in healthy tissues, it can be potentially used for early detection of cancer. Contemporary molecular methods allow to analyze expression of dozens of genes in the cancerous growth tissues and to compare the obtained picture with the “gene portrait” of normal cells. Certainly, the Kaiso gene is not the only one that can be used for such diagnosticums. The tumour represents a very heterogeneous and rather dynamic system, which requires knowledge of almost the entire “genetic portrait” of 28,000 genes.

It is thought that there are other between 10 and 30 key genes which can also serve as markers of tumour characteristics. This will save resources and time, relieving the necessity of analyzing the entire multithousand genome.

In cancer therapy, chimeric Kaiso protein could be created. The ordinary Kaiso protein (via DNA methylated binding) inhibits the work of cancer suppressor genes. However, it is possible, using the same properties of the protein, to make it not suppress, but reinforce the work of these genes. This is what the researchers are striving to achieve.

“Although, there are hidden pitfalls here,” explains Anna Prokhorchuk, project manager. “It is necessary to make chimeric Kaiso work only to activate cancer suppressor genes, not the other methylated DNA sequences. This is what we are working at in the Bioengineering Centre jointly with American colleagues.” The ultimate aim of the investigation is to scrutinize the possibility for using Kaiso protein as a target for directional anticancer therapy.

Sources:

Molecular and Cellular Biology, January 2006, p. 199-208, Vol. 26, No. 1
Kaiso-deficient mice show resistance to intestinal cancer. Prokhortchouk Anna, et al. Mol Cell Biol. 2006 Jan;26(1):199-208. Wellcome Trust Centre for Cell Biology, Edinburgh University, Edinburgh, UK; Cardiff School of Biosciences, Cardiff University, Cardiff, Wales, UK; Center “Bioengineering,” Russian Academy of Sciences, Moscow, Russia; Department of Developmental and Molecular Biology and Medical Oncology, Albert Einstein College of Medicine, Bronx, New York; Institute for Stem Cell Research, University of Edinburgh, UK; Montefiore Medical Center, Albert Einstein Cancer Center, Bronx, New York, USA.

Jan 13, 2005 www.informnauka.ru

Related:
Nucleic Acids Res. 2002 Jul 1;30(13):2911-9. Click here to read full free text
The p120(ctn)-binding partner Kaiso is a bi-modal DNA-binding protein that recognizes both a sequence-specific consensus and methylated CpG dinucleotides.
Daniel JM, Spring CM, Crawford HC, Reynolds AB, Baig A. McMaster University, Hamilton, ON L8S 4K1, Canada.

Hybridoma. 2001 Jun;20(3):159-66. Monoclonal antibodies to Kaiso: a novel transcription factor and p120ctn-binding protein.
Daniel JM, et al. McMaster University, Hamilton, ON L8S 4K1 Canada.

Genes & Development Vol. 15, No. 13, pp. 1613-1618, July 1, 2001
The p120 catenin partner Kaiso is a DNA methylation-dependent transcriptional repressor
Anna Prokhortchouk, et al. Group of Transcriptional Control and Oncogenesis, Institute of Gene Biology, Moscow, Russia; 2 Wellcome Trust Centre for Cell Biology, Edinburgh University, Edinburgh, Scotland, UK; 3 Protein and Peptide group, EMBL, D-69117 Heidelberg, Germany; 4 Department of Molecular Cancer Genetics, Institute of Gene Biology, Moscow, Russia.