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Contact Information:

Markku Heikinheimo
M.D., Ph.D.
pediatrician, pediatric hematologist, Professor of Pediatrics

Head of the National Clinical Graduate School

Head of the Clinical Graduate School in Pediatrics and Obstetrics/Gynecology (PEGY) (co-chaired with prof. Jorma Paavonen)

Laboratory:
Biomedicum Helsinki 2U
P.O. Box 63 (Tukholmankatu 8)
00014 University of Helsinki
Finland

Office:
Children's Hospital
P.O. Box 22
00014 University of Helsinki
Finland

Tel. +358 9 471 71983
Fax +358 9 471 71947

E-mail:
firstname.surname@helsinki.fi

Visiting professor of pediatrics, Division of Pediatric
Hematology / Oncology,
Dept. of Pediatrics,
Washington University
Medical School,
St. Louis, MO, USA

Welcome!

Growth and development requires precise control of gene expression. Abnormalities in transcription have been linked to a variety of human diseases, including birth defects and neoplasia. Our studies focus on the GATA transcription factors, which are zinc finger proteins recognizing a consensus DNA sequence (A/T)GATA(A/G), known as GATA-motif, an essential cis -acting element in the promoters and enhancers of a variety of genes. These proteins form two subgroups based on their sequence homology and expression patterns. The first subgroup, consisting of GATA-1, -2, and -3, is essential for normal hematopoiesis. The second subgroup members, namely GATA-4, -5, and -6, are expressed in the heart, gut epithelium, yolk sac endoderm, and several endocrine organs. The specificity of gene regulation by GATA factors is in part achieved by cofactors acting in concert with them. Two related factors, FOG-1 and FOG-2 (FOG for friend-of-GATA), bind to one of the two zinc fingers of the GATA proteins to activate or repress the gene transactivation by the GATA proteins. The essential role of GATA factors in the development of endocrine and endoderm derived organs has begun to unravel during the past years, but their ultimate target genes and their role in human endocrine and endoderm disease and cancer has still remained largely unknown. The long-term goal of our projects is to recognize potential targets for future diagnostics and therapy.

The major previous achievements of our research are:

• GATA-4 has been identified as a central factor in mammalian heart development and gene regulation
• The expression of GATA-4, GATA-6, and FOG-2 have been elucidated in the development of gonads and adrenal gland
• Using mouse models and human tumor tissues coupled with detailed clinical data, the important role of GATA-4 and GATA-6 in the development of adrenal cancer have been detailed
• GATA-4 and its target gene Anti-Müllerian hormone (AMH; also known as MIS) have been implicated in the granulosa cell tumor (GCT) pathogenesis
• In GCTs, GATA-4 has been shown to act as an anti-apoptotic factor. GATA-4 exerts its effects through Bcl-2 and TRAIL controlled antiapoptotic and apoptotic pathways, respectively.
• The role of GATA factors in the development and function of the visceral endoderm / yolk sac have been elucidated, and their potential role in human yolk sac tumors has been explored
• GATA-4 has been implicated in the mouse models for and in the human congenital diagphragmatic hernia
• The expression patterns of GATA-4, -5 and -6 have been associated with normal gastrointestinal development, regeneration and malignant trasformation. Furthermore, GATA-4 has been linked to TGF-ß signaling in human inflammatory bowel disease.

Studies on other issues than GATA factors have e.g. A) suggested essential roles for Fgf8 (Fgf for fibroblast growth factor) in the development of limbs, cranial and CNS structures, B) described a new genetic form of immunodeficiency, i.e. CD45 deficiency and C) described clinical features and developments in the treatment of embryonic tumors.

Page updated May 6, 2011

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