Post-transcriptional gene expression regulation ---> Translational control ---> Cancer research
Present work at:
1) Medical Centre of Postgraduate Education (MCPE), Department of Biochemistry and Molecular Biology, ul. Marymoncka 99/103, 01-813 Warsaw, Poland, and
2) BioTe21, Laboratory of Molecular Medical Biology (BioTe21), Centre for Innovations, Technology Transfer and University Development, ul. Gronostajowa 7, 30-387 Cracow, Poland,
Medical Centre of Postgraduate Education
Research of CMKP's Laboratory of Molecular Biology is focused on three major topics: a) molecular mechanism of cancerogenesis, b) hormonal regulation of cancerogenesis and c) molecular mechanism of thyroid hormone action, and more specific topics: 1) role of untranslated regions (UTR) in regulation of protein synthesis in cancer, 2) disturbances of alternative splicing in cancer and 3) role of microRNA in regulation of protein synthesis in cancer.
The laboratory posses a large collection of ccRCC specimens with respective control tissues, as well as Bank of RNA, cDNA and DNA isolated from the ccRCC tissues and controls. Another type of material are cell lines of ccRCC: Caki-1, Caki-2 and control health line HK-2.
One of the aims of the ongoing work is to elucidate the role of thyroid hormone in the process of neogenesis. The model we use is clear cell renal cell carcinoma (ccRCC). ccRCC is one the most frequent renal cancers (75%-80% of all cases). It is also one of the most aggressive cancers and is characterized by high mortality which is a result of late diagnosis. The molecular mechanism of thyroid hormone action in cancerogenesis is not well understood. The research in our laboratory showed that the molecular pathway of T3 is disturbed in ccRCC. This encompasses Non thyroidal illness syndrome (NTIS), frequently observed in ccRCC patients, disturbance of TRs and D1 expression in ccRCC tumors, as well as mutations in TRs cloned from ccRCC tumors.
Thyroid hormone receptor β1 (TRβ1) is a hormone-dependent transcription factor activated by 3,5,3'-Ltriiodothyronine (T3). TRβ1 functions as a tumor suppressor and disturbances of the THRB gene are frequent findings in cancer. Translational control mediated by untranslated regions (UTRs) regulates cell proliferation, metabolism and responses to cellular stress, processes that are involved in carcinogenesis. We determined TRβ1 expression and alternative splicing of TRβ1 5′ and 3′ UTRs in ccRCC and control tissue together with expression of the type 1 deiodinase enzyme (coded by DIO1, a TRβ1 target gene). Tissue concentrations of T3 (which are generated in part by D1) and expression of miRNA-204 (an mRNA inhibitor for which a putative interaction site was identified in the TRβ1 3′UTR) were also determined. TRβ1 mRNA and protein levels were reduced by 70% and 91% in ccRCC and accompanied by absent D1 protein, a 58% reduction in tissue T3 concentration and 2-fold increase in miRNA-204. Structural analysis of TRβ1 UTR variants indicated that reduced TRβ1 expression may be maintained in ccRCC by posttranscriptional mechanisms involving 5′UTRs and miRNA-204. The tumor suppressor activity of TRβ1 indicates that reduced TRβ1 expression and tissue hypothyroidism in ccRCC tumors is likely to be involved in the process of carcinogenesis or in maintaining a proliferative advantage to malignant cells.
BioTe21, Laboratory of Molecular Medical Biology
BioTe21 is a laboratory with the experience in the field of molecular medicine, development of new genetic diagnostics and innovative biotechnologies.Laboratory of Molecular Medical Biology is focused on elaboration of a new generation of therapeutics based on RNA interference phenomenon and recombinant proteins. The laboratory's strategic aim is to create a technological and scientific resource base allowing development of useful bioinformatic projections as well as elaboration and implementation of new biotechnologies with particular acknowledgement of applications utilised in molecular medicine and gene therapy.
The basic activities of our Laboratory of Genetics are divided into four main areas:
- Nucleic Acid Synthesis and Sequencing,
- Genetic identification,
- Medical Genetic diagnostics,
- Elaboration and implementation of innovative biotechnologies including cancer gene therapies.
The laboratory is also interested in researching use and implementation of scientific discoveries in biotechnology and medicine based on rudimentary studies of genome, transcriptome and proteome.
In recognition of the quality of our research we have been awarded international certificates GEDNAP in genetic analysis of STR systems as well as the certificate in mitochondrial DNA sequence analysis in variable regions of mtDNA-HVI and mtDNA-HVII. Professional experience and knowledge of our team within the field of biochemistry, biotechnology, molecular medicine and genetic analysis guarantee high quality of our research as well as certainty of results.Our team was involved in many scientific projects finalized with publications of high-scientific importance.
My special research interests: Translational Control in Cancers
Translational control is a mechanism of protein synthesis regulation emerging as an important target for new therapeutics. Naturally occurring microRNAs and synthetic small inhibitory RNAs are the most recognized regulatory molecules acting via RNA interference. Surprisingly, recent studies have shown that interfering RNAs may also activate gene transcription. In my last research project, we demonstrated for the first time that the newly discovered phenomenon of small RNA-induced gene activation can also enhance protein translation by acting at sequence-specific targets within the messenger RNA 5’-untranslated region (5’UTR). A a set of oligonucleotide-based trans-acting factors (dGoligos) was designed, specifically targeting alternatively spliced 5’UTRs in transcripts expressed from the several genes, encoding thyroid suppressors. For instance, the in vitro translation efficiency of reporter constructs containing alternative TRß1 5’UTRs (the work performed in MCPE and BioTe21) was increased by up to more than 6.5-fold following exposure to specific dGoligos. Our report (now under editorial consideration) would be the first showing a method for gene-specific translation enhancement using selective trans-acting factors designed to target specific 5’UTR cis-acting elements of high regulatory potential. This simple strategy may be developed in the future to complement other available methods for gene expression regulation including gene silencing. The dGoligo-mediated enhancement of protein expression has the potential to be transferred to increase the translation efficiency of any suitable target gene and may have future application in gene therapy strategies to enhance expression of proteins such as tumor suppressors.