Supervisor: Prof. Dr. Michael Gekle and PD Dr. Gerald Schwerdt
Specific aim(s)/topic(s)
(1) Characterizing the functional principle of the long non-coding RNA lncWISP1
(2) Impact of lncWISP1 on cellular phenotypes
Background and significance
Chronic interstitial deregulation of tissue homeostasis (parainflammation) is a risk factor for fibrosis and carcinogenesis. The mechanisms of unbalanced tissue homeostasis involve altered transcriptional and post-transcriptional regulatory mechanisms, including non-coding RNAs such as microRNAs (miR) or long non-coding RNAs (lncRNAs). LncRNAs belong to a rapidly growing class of RNAs and are defined as non-coding transcripts longer than 200 nucleotides. They are involved in processes like chromatin modification, transcriptional and post-transcriptional gene regulation. For example, lncRNAs have been shown to sequester miRNAs and thereby promote the expression of miRNA-target genes (sponge-like action).
Wnt1-inducible signaling pathway protein 1 (WISP1) is involved in organ development but also in fibrogenic and cancerous tissue alterations. It belongs to the CCN family of connective tissue growth factors and is canonically regulated by the Wnt1/β-catenin pathway. Also, some splice variants and other alternative transcripts expressed from the WISP1 locus with mostly unknown function have been described. Some of these appear to act as non-coding RNAs. Our recent data showed that an alternative WISP1 transcript is upregulated by different cell stressors in renal cells leading to the increased formation of extracellular matrix (ECM) components such as collagens. This suggests a role of the WISP1 locus in pathological cellular processes, in particular fibrosis. Accordingly, the identification and characterization of triggers and mechanisms involved in WISP1 RNA-induced deregulation of tissue homeostasis may contribute to the understanding of organ and tissue remodeling and malfunction. These studies have to address: 1) relevant cell stressors; 2) signaling pathways involved in non-coding RNA expression; 3) interactions of non-coding RNAs and their crosstalk with target gene expression.
Supervisor: Prof. Dr. Claudia Großmann and Dr. Barbara Schreier
Specific aim(s)/topic(s)
(1) Mechanisms and role of EGFR for cardiovascular miR-221/222 deregulation
(2) Cellular and functional consequences of EGFR-dependent miR-221/222 deregulation
Background and significance
The EGFR is a ubiquitously expressed receptor tyrosine kinase that can be activated by different ligands like EGF and/or is trans-activated by a variety of stimuli including G-protein-coupled receptors and cellular stress; thus, the EGFR is an important interconnection. In the cardiovascular system, an association of EGFR with impaired vascular and cardiac function and parainflammatory remodeling processes has been made based on clinical and experimental data of pharmacological EGFR inhibitors and mice with reduced EGFR tyrosine kinase activity. These findings remain partially contradictory and the underlying molecular mechanisms are not completely understood.
In recent years, miRNAs have been implicated in the regulation of pathological cardiac and vascular phenotypes, and the EGFR signaling cascade has been suggested as a regulator of miR expression. One of the most prominent miR clusters associated with cardiovascular homeostasis and pathology is miR-221/222. These miRs also show altered expression in the aorta and heart of mice with targeted deletion of EGFR, suggesting an involvement of these miRs in EGFR’s role in the cardiovascular system.
Supervisor: Prof. Dr. Stefan Hüttelmaier (Speaker of the GRK1591)
Specific aim(s)/topic(s)
(1) The role of IGF2BP2 in controlling glucose homeostasis and diabetes
(2) The role of IGF2BP2 in growth control and tumor cell fate
Background and significance
One major class of RBPs associated with cancer and potentially diabetes is the IGF2 mRNA binding protein family (IGF2BPs). In humans, the IGF2BP family comprises three members, two of which, IGF2BP1 and IGF2BP3, are classified as oncofetal proteins with de novo synthesis in various solid cancers. In vitro studies suggest IGF2BP1 acts as a pro-metastatic oncogene promoting mesenchymal-like tumor cell properties including enforced migratory capacity as well as tumor cell survival. In contrast, the only family member observed in non-transformed adult mouse tissue, the IGF2BP2 paralogue, was suggested to modulate cell growth and glucose homeostasis. Genetic studies revealed that single nucleotide polymorphisms (SNPs) in the human IGF2BP2 gene are correlated with a modestly elevated risk of type 2 diabetes (T2D). In vitro, IGF2BP2 was shown to promote IGF2 mRNA translation in an mTOR-dependent manner. This suggests the protein to promote cell growth. However, in vivo validation of both, IGF2BP2-dependent control of glucose homeostasis and/or cell growth, is still lacking. Moreover, the molecular mechanisms and downstream effectors via which IGF2BP2 exerts its postulated regulatory roles remain largely elusive.
Supervisor: Prof. Dr. Barbara Seliger
Specific aim(s)/topic(s)
(1) Identification of HLA class I targeting miRs, their functional characterization and clinical significance
(2) Identification and characterization of the function of RNA-binding proteins controlling components of the antigen processing and presentation machinery
Background and significance
Hematologic and solid tumors have developed strategies to escape immune surveillance, including abnormalities in the classical HLA antigens, which are directly associated with metastatic properties, disease progression and poor patient survival. The underlying molecular mechanisms of altered HLA class I surface antigen expression are only rarely associated with structural alterations in components of the HLA class I antigen processing and presentation machinery (APM), but are often due to their deregulated expression, which can occur at the epigenetic, transcriptional and post-transcriptional level. Altered gene expression in tumors can be controlled by diverse mechanisms including post-transcriptional mechanisms involving RNA-binding proteins (RBP) as well as microRNAs (miRs). Indeed, miRs have been identified that regulate the expression of immunomodulatory molecules, thereby also affecting the immune responses. While the post-transcriptional regulation of HLA class I APM components has not yet been defined in detail, their regulation appears to be a key process in tumor development by altering the immunogenicity of tumors. The expression and function of different HLA class I APM components, in particular of the peptide transporters TAP1 and TAP2 as well as of tapasin, has been found to be impaired in many tumors, but miRs and RBPs targeting these molecules have not yet been identified in these malignancies. Thus, miRs and RBPs that control TAP and/or tapasin in tumor cells will be identified.