Author:

Abstract:

The “High Mobility Group (HMG)” protein family consists of four members: HMGA1a, HMGA1b and HMGA1c, which result from alternative splicing from one gene and HMGA2 which is encoded for by another gene. HMGA proteins are characterized by three DNA-binding domains, called AT-hooks, and an acidic carboxy-terminal tail. HMGA proteins are architectural transcriptional factors that both positively and negatively regulate the transcription of a variety of genes. They do not display direct transcriptional activation capacity, but regulate gene expression by changing the DNA conformation by binding to AT-rich regions in the DNA and/or direct interaction with several transcription factors. In this way, they influence a diverse array of normal biological processes including cell growth, proliferation, differentiation and cell death. Both HMGA1 and HMGA2 are hardly detectable in normal adult tissue but are abundantly and ubiquitously expressed during embryonic development. In malignant epithelial tumors as well as in leukaemias, however, expression of HMGA1 is again elevated to embryonic levels thus presumably leading to ectopic expression of (fetal) target genes. HMGA2 overexpression also has a causal role in inducing neoplasias. Besides overexpression of full length HMGA proteins in different tumors, the HMGA genes are often involved in chromosomal rearrangements. Such translocations are mostly detected in benign tumors of mesenchymal origin and are believed to be one of the most common chromosomal rearrangements in human neoplasias. Since HMGA1 upregulation is a common feature in a wide variety of carcinomas, it is important to have insight in the mechanism(s) behind the elevated expression of HMGA1. However, at the start of my thesis research, little was known about transcriptional regulation of HMGA1 in both normal cells as well as in cancer cells. Likewise, the exact role played by the HMGA proteins in the development of cancer is still unknown. With the work described in this thesis, we succeeded to get more insight in the potential role of HMGA1 and HMGA2 in cell growth and tumorigenesis. In the first part of this thesis, we wanted to elucidate the transcriptional regulation of HMGA1 in both normal cells as well as in cancer cells. Therefore, we have cloned and functionally analyzed the TATA-less 5’-flanking regulatory region of human