The two decades of research on the cellular functions of the evolutionarily conserved tid tumor suppressor gene which we have originally identified with the help of the fruit fly Drosophila melanogaster brought some insight into the actions of the Tid-proteins in maintaining the homeostasis of cellular signaling mediated by receptors (Ptc, ErbB2, MuSK, IFNγR2,TRPC6), tyrosin kinases (TRKA, c-Met), intracellular signal transmitters (APC, VHL, RAS-GAP) and transcriptional regulators (NFκB, Tax, E7, p53). The data available strongly suggests that the diverse molecular contexts the human, mouse and fly Tid proteins have been shown to be involved in are of essential relevance for both the normal and adult development and a variety of pathologies, among them diverse cancers as well as immune and neurodegenerative diseases.
The Drosophila, man (h) and mouse (m) tid genes encode three transcripts (long: L, intermediate: I und short: S) translated into three cytosolic (Tid-LC, Tid-IC,Tid-SC) and three mitochondrial proteins (Tid-Lm, Tid-Im, Tid-Sm). Interestingly, the cytosolic Tid proteins L and I have been found to interact simultaneously with the same physiological partner. The cellular consequences of this phenomenon are unknown. The question whether the action of the two proteins is independent, synergistic or contradictory in the same cellular process has to be answered. The cellular role of the S form is still enigmatic and remains to be discovered. Thus, the main topic of our current research is to elucidate the cell specific role of the distinct Tid proteins in vivo in developmental and cancer related contexts with the help of splice form specific transgenic mtid-knock-in and -KO lines which we have generated for these purposes.
The further to day not investigated aspect of tid function we are interested in is the transcriptional regulation of the gene. In this context we isolated potential htid-promoter binding proteins and are currently investigating their involvement in the regulation of htid transcription.
Kurzik-Dumke U, Hörner M, Nicotra MR, Koslowski M, Natali PG. 2010. In vivo evidence of htid suppressive activity on ErbB-2 in breast cancers over expressing the receptor. J.Translational Medicine 8:58-71.
Kurzik-Dumke U, Hörner M, Nicotra MR, Czaja J, Simiantonaki N, Koslowski M, Natali PG. 2008. Progression of colorectal cancers correlates with overexpression and loss of polarization of expression of the htid-1 tumor suppressor. Int. J. Mol. Oncol. 21:19-21.
Simiantonaki N, Taxeidis M, Jayasinghe C, Kurzik-Dumke U, Kirkpatrick CJ. 2008. Hypoxia-inducible factor 1α expression during colorectal carcinogenesis and tumor progression. BMC Cancer 3:320-331.
Kurzik-Dumke U, Czaja J. 2007. Htid-1, the human homolog of the Drosophila l(2)tid tumor suppressor, defines a novel physiological role of APC. Cellular Signaling 19:1973-1985.
Simiantonaki N, Kurzik-Dumke U, Karyofili E, Jayasinghe C, Kirkpatrick CJ. 2007. Reduced expression of TLR4 is associated with the metastatic status of human colorectal cancer. Int. Journal of Mol. Medicine 20:21-29.
Simiantonaki N, Kurzik-Dumke U, Karyofili E, Jayasinghe C, Michel-Schmidt R, Kirkpatrick CJ. 2007. Loss of E-Cadherin in the vicinity of necrosis in colorectal carcinomas: Association with NF-κB expression. Int. Journal Oncol. 31:269-275.
Canamasas I, Debes A, Natali PG, Kurzik-Dumke U. 2003. Understanding human cancer using Drosophila: Tid47, a cytosolic product of the dnaJ-like tumor suppressor gene l(2)tid, is a novel molecular partner of Patched related to skin cancer. JBC 278:30952-30960.
Chapple JP, Hardcastle AJ, Kurzik-Dumke U, Collier DA, Cheetham ME. 1999. Assignment of the neuronal cochaperone, HSJ1, to human chromosome band(s) 2q32-34 by in situ hybridization and with somatic cell and radiation hybrids to between D2S295 and D2S339. Cytogenet. Cell Genet. 86:62-63.
Kurzik-Dumke U, Schick Ch, Rzepka R, Melchers I. 1999. Overexpression of human homologues of the bacterial DnaJ Chaperone in the synovial tissue of patients with rheumatoid arthritis. Arthritis & Rheumatism 42:210-220.
Kurzik-Dumke U, Debes A, Kaymer M, Dienes P. 1998. Mitochondrial localization and temporal expression of the Drosophila melanogaster DnaJ homologous tumor suppressor Tid56. Cell Stress & Chaperones 3:12-27.
Kaymer M, Debes A, Kress H, Kurzik-Dumke U. 1997. Sequence, molecular organization and products of the Drosophila virilis homologs of the Drosophila melanogaster nested genes lethal(2)tumorous imaginal discs (l(2)tid) and lethal(2) neighbour of tid (l(2)not). Gene 204:91-103.
Kurzik-Dumke U, Gundacker D, Kaymer M, Debes A, Labitzke K. 1997. Gene within gene configuration and expression pattern of the Drosophila melanogaster genes lethal(2)neighbour of tid (l(2)not) and lethal(2)relative of tid (l(2)rot). Gene 200:45-58.
Kurzik-Dumke U, Schirmacher P, Bobkiewicz W, Kedzia H, Gozdzicka-Jόzefiak A. 1997. Preliminary study on expression of the human hTid protein, a homolog of the Drosophila melanogaster tumor suppressor Tid56 in various tumors. The Cancer J. 10:56-62.
Gateff E, Kurzik-Dumke U, Wismar J, Löffler T, Habtemichael N, Konrad L, Dreschers S, Kaiser S, Protin U. 1996. Drosophila: Differentiation genes instrumental in tumor suppression. Int. J. Dev. Biol. 40:149-156.
Kurzik-Dumke U, Neubauer M, Debes A. 1996. Identification of a novel Drosophila melanogaster heat shock gene, lethal(2)denticleless (l(2)dtl), coding for a 83 kDa protein. Gene 171:163-170.
Kurzik-Dumke U, Zengerle A. 1996. Identification of a novel Drosophila melanogaster gene, angel, a member of a nested gene cluster at locus 59F4,5. BBA 1308:177-181.
Kurzik-Dumke U, Gundacker D, Rentrop M, Gateff, E. 1995. Tumor suppression in Drosophila is causally related to the function of the lethal(2)tumorous imaginal discs gene, a dnaJ homolog. Dev. Genetics 16:64-76.
Kurzik-Dumke U, Lohmann E. 1995. Sequence of the new Drosophila melanogaster small heat-shock-related gene, lethal(2)essential for life (l(2)efl), at locus 59F4,5. Gene 154:171-175.
Kurzik-Dumke U, Müllenbach R, Holzmann K, Gateff E, Blin N, Dooley S. 1993. Genetic mapping of a new Drosophila fos-related sequence isolated via PCR technology using mammalian c-fos specific primers. Drosophila Inf. Serv. 72:139-142.
Gundacker D, Phannavong B, Vef O, Gateff E, Kurzik-Dumke, U. 1993. Genetic and molecular characterization of breakpoints of five deficiencies isolated in the genomic region 59F5-60A. Drosophila Inf. Serv. 72:129-131.
Kurzik-Dumke U, Phannavong B, Gundacker D, Gateff E. 1992. Genetic, cytogenetic and developmental analysis of the Drosophila melanogaster tumor suppressor gene lethal(2)tumorous imaginal discs (l(2)tid). Differentiation 51:91-104.
Roebroek AJM, Creemers JWM, Pauli IGL, Kurzik-Dumke U, Rentrop M, Gateff E, Leunissen JAM, Van de Ven WJM. 1992. Cloning and Functional Expression of Dfurin2, a Subtilisin-like Proprotein Processing Enzyme of Drosophila melanogaster with Multiple Repeats of a Cysteine Motif. J. Biol. Chem. 267:17208-17215.
Kurzik-Dumke U, Gundacker D, Debes A. 1997. Tid56. In: Guidebook to Molecular Chaperones and Protein Folding Factors, Gething, M.-J. (Ed.), Sambrook & Tooze Publication, Oxford University Press, Oxford, pp. 176-181.
Kurzik-Dumke U. 1996. Nested gene arrangement of the Drosophila melanogaster tumor suppressor locus lethal(2)tumorous imaginal discs (l(2)tid) consisting of at least three Genes. In: Control Mechanisms of Carcinogenesis, Hengstler, J. and Oesch, F. (Eds.), Thieme Verlag, pp. 224-244.