@phdthesis{3070838,
  abstract     = {{Cancer is caused by the accumulation of genetic and epigenetic mutations in genes that normally play a role in the regulation of cell proliferation, the control of cell death or the repair of damaged DNA. Depending on how they affect each process, these genes can be grouped into two general categories: tumor suppressor genes (growth inhibitory) and proto-oncogenes (growth promoting). Many additional genes contribute to invasion and metastasis when malignant cancers disseminate in the body. Unraveling the mechanisms how tumor suppressor genes, oncogenes and invasion/metastasis genes participate in the formation and progression of tumors has provided a solid foundation for understanding the various steps in carcinogenesis and cancer dissemination. Nonetheless, further research is needed to elucidate the molecular mechanisms and signaling pathways involved in cancer formation and progression in more detail, with the ultimate goal to develop more specific and safer cancer therapeutics.
In recent years, both direct and indirect evidence has accumulated that δ-protocadherins play important roles during tumorigenesis and tumor progression. Especially protocadherin-10 (PCDH10) was shown to be silenced in a variety of human cancers by epigenetic mechanisms, which is a characteristic feature for the loss of gene function in cancer. Although in vitro studies demonstrated that PCDH10 can inhibit tumor cell proliferation, cell migration and invasive potential, the putative tumor-suppressive role of PCDH10 has not been investigated in vivo and the mechanisms and signaling pathways involved have not been elucidated yet. Therefore, I have generated two conditional knockout mouse models for Pcdh10, which allows me to delete either all or only the long isoforms of Pcdh10 constitutively or in a tissue-specific manner. Mice with ubiquitous loss of either all or only long Pcdh10 isoforms turned out to be viable and fertile and did not show any obvious developmental defects. Interestingly, complete loss of Pcdh10 very early in development led to the upregulation of several other δ-protocadherin family members, indicating that they might take over the function of Pcdh10 during mouse development. In contrast, loss of only the long Pcdh10 isoforms led to the upregulation of the preserved short Pcdh10 isoform but not other δ-protocadherins, suggesting that the long isoforms, including the conserved cytoplasmic CM1 and CM2 motifs, are not essentially required during normal mouse development.
The availability of these unique mice with floxed Pcdh10 alleles opens interesting opportunities for research on human pathologies involving PCDH10 deficiencies. So, in order to study the effects of Pcdh10 loss on cancer development, I intended to combine tissue-specific deletion of Pcdh10 with activation or deletion of genes well known to be involved in oncogenic signaling pathways. Quantitative mRNA expression analysis revealed that, unlike in human tissues, mouse Pcdh10 expression is mainly restricted to the brain. Therefore, my current approach is to generate a mouse model of medulloblastoma, a tumor with reported silencing of PCDH10 in humans. 
In order to identify intracellular interaction partners of PCDH10 and to unravel the involvement of PCHD10 in normal and pathogenic signaling pathways, I performed protein-protein interaction screens in yeast and mammalian systems. However, various drawbacks in these two systems resulted only in the identification of false positives and no genuine interacting proteins. However, by screening several putative interacting proteins of other δ-protocadherins, I identified the dynein light chain, Tctex-type 1 (DYNLT1) as a reliable interactor of PCDH10. I found evidence that the PCDH10 interaction is dynein-dependent, i.e. occurs with DYNLT1 in the dynein motor complex, and that both proteins colocalize at perinuclear regions in HeLa cells, which suggests a cargo transport function for DYNLT1 with respect to PCDH10. Although I could not localize DYNLT1 to the plasma membrane so far, DYNLT1 has been reported to be enriched at cell-cell contact sites. Since I showed that at least part of the PCDH10 proteins is localized at the plasma membrane and at cell-cell contacts, a function of the PCDH10-DYNLT1 interaction at the plasma membrane is still conceivable.
The molecular mechanisms and signaling pathways explaining the association of PCDH10 defects with human cancer development are still poorly understood. Therefore, the generation of in vivo cancer models for PCDH10-related cancers and the identification and characterization of intracellular interaction partners of PCDH10, as described in this Ph.D. thesis, will provide us with most valuable insights into the putative tumor suppressor role of PCDH10.}},
  author       = {{Kahr, Irene}},
  language     = {{eng}},
  pages        = {{295}},
  publisher    = {{Ghent University. Faculty of Sciences}},
  school       = {{Ghent University}},
  title        = {{Functional analysis of the candidate tumor suppressor protein protocadherin-10}},
  year         = {{2012}},
}