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Diagnostic Test-Systems for Anti-Cancer Therapy

#2593


Studies on р21Waf1/Cip1 Role in Cellular Cycle Regulation and in Apoptosis and Development of Diagnostic Test-Systems for Anti-Cancer Therapy Based on the Data Obtained

Tech Area / Field

  • MED-DID/Diagnostics & Devices/Medicine
  • BIO-CGM/Cytology, Genetics and Molecular Biology/Biotechnology

Status
8 Project completed

Registration date
22.08.2002

Completion date
13.10.2009

Senior Project Manager
Melnikov V G

Leading Institute
Institute of Theoretical and Experimental Biophysics, Russia, Moscow reg., Puschino

Supporting institutes

  • Institute of Bioorganic Chemistry, Russia, Moscow\nInstitute of Immunological Engineering, Russia, Moscow reg., Lyubuchany

Collaborators

  • University of Medicine and Dentistry of New Jersey / Robert Wood Johnson Medical School, USA, NJ, Piscataway\nCLONTECHLaboratories, Inc. / BD Biosciences, USA, CA, Palo Alto

Project summary

The aim of the studies is elucidation of р21W af1/Cip1 role in cellular cycle regulation and in apoptosis and development of diagnostic test-systems for anti-cancer therapy based on the data obtained.

One of the most important tasks of contemporary experimental biology and medicine is the study of interaction of molecular mechanisms of cellular death and cellular cycle. Elucidation of this problem is of importance for solving of such problems as treatment of various forms of pathology connected with disturbances of cellular cycle and/or apoptosis, particularly malignant neoplasms, autoimmune, neurodegenerative and other deviations.

Cellular cycle mechanism has been studied rather well. Key proteins regulating this process have been registered. Cyclin complexes and cyclin-dependent kinases and transcriptional factors of E2F family are considered as positive regulators of the cellular cycle, but tumor suppressors р53 and pRB and inhibitors of cyclin-kinase complexes р15, р16, р21, р27 are considered negative ones.

Lately, thanks to application of contemporary techniques of molecular and cellular biology, genes and their products participating in apoptosis realization have been identified. Among them, proteins both up-and-down-regulating cellular death were found. Proteins containing so-called “death domain”, such as Fas, MORT1/FADD, RIP; various caspases, transcriptional factors - р53, AP-1, ATF-1; pro-apoptosis proteins of Bcl2 family- Bax, Bak, Bad, Bid, and many others are considered up-regulating. Inhibitor proteins, such as SODD, с-IAPs, c-FLIPs; apoptosis proteins of Bcl2 family – Bcl2, BclXL; transcriptional factors NF-kB, Est-1 and others are included into the second group of proteins contributed to prevention of physiological cellular death.

р21Waf1/Cip1protein influencing processes of cellular cycle and apoptosis takes a special part. Information that is now available testifies р21Waf1/Cip1 ability to suppress apoptosis in pRB+and p53+ cells. Inactivation of the gene encoding р21Waf1/Cip1protein results in up-regulation of sensitivity of cells to apoptosis signals, while enhanced expression of р21Waf1/Cip1 protein down-regulates cellular sensitivity to apoptosis. In both cases sharp changes in distribution of cells according phases of cellular cycle are observed. р21Waf1/Cip1protein is supposed to be one of the possible candidates for the role of the mediator of these two processes.

Available for today data make it possible to explain the mechanism of action of р21Waf1/Cip1protein inducing down-regulation of cell sensitivity with functional proteins pRB and р53, to cytotoxic agents. But in such cases when pRB and p53 proteins are unfunctional, for example in tumor cells, р21Waf1/Cip1 produces fully opposite effect. Enhanced expression of р21Waf1/Cip1 protein in such cells results in up-regulation of sensitivity to signals induced apoptosis.

We intend in our proposal to:

– analyze expression and function of proteins defining pro- or anti-apoptosis effect of р21Waf1/Cip1;


– find out role and function of р21Waf1/Cip1 in realization of cellular death induced by various cytotoxic factors;
– define molecular targets for р21Waf1/Cip1effect;
– develop recommendations for analysis of р21Waf1/Cip1 expression and functionally connected with it proteins in transformed cells;
– construct samples of genetic and immune-chemical diagnostic test-systems for anti-cancer therapy.


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