1. ¹Research Program of Molecular Neurology, Biomedicum-Helsinki, University of Helsinki, Helsinki, Finland
2. ²Research Program of Genome-Scale Biology, Biomedicum-Helsinki, University of Helsinki, Helsinki, Finland
3. ³Department of Medical Genetics, University of Helsinki, Helsinki, Finland
4. ⁴Department of Molecular Medicine, National Public Health Institute, Helsinki, Finland
5. ⁵Department of Mental Health and Alcohol Research, National Public Health Institute, Helsinki, Finland
6. ⁶Department of Neurology, Helsinki University Central Hospital, Helsinki, Finland

Correspondence: Professor A Suomalainen, Biomedicum-Helsinki, University of Helsinki, Room c523B, Haartmaninkatu 8, Helsinki 00290, Finland. E-mail: Anu.wartiovaara@helsinki.fi

Received 16 May 2008; Revised 10 December 2008; Accepted 11 December 2008; Published online 19 January 2009.

Abstract

Defects of metabolic enzymes result in a variety of manifestations not logically explained by the primary metabolic function. Dominant defects of fumarate hydratase (FH) result in predisposition to cutaneous and uterine leiomyomas, and renal cell cancer. FH is a metabolic enzyme of the tricarboxylic acid cycle, and its tumor-suppressor mechanism is not fully understood. We compared the consequences of FH deficiency and respiratory chain (RC) deficiency using global expression pattern of diploid primary fibroblasts. This approach utilized the information that RC defects do not seem to predispose to tumorigenesis, and the aim was to identify FH-specific signaling effects that might have relevance to tumor formation. These results were then compared to global expression patterns of FH-deficient and sporadic uterine leiomyoma data sets. We show here that FH-deficient fibroblasts share a common transcriptional fingerprint with FH-deficient and sporadic leiomyomas, highlighting the downregulation of serum response factor (SRF)-regulated transcripts, particularly the FOS–JUNB pathway. We confirmed the downregulation of this pathway at transcriptional and protein level. SRF has a fundamental function in the differentiation of smooth muscle progenitor cells, and its downregulation both in diploid FH-deficient primary fibroblasts and in leiomyomas suggests an early function in the mechanism of uterine leiomyoma formation in FH deficiency. Concordantly, the phosphorylated form of SRF, known to activate transcription, is undetectable in leiomyomas whereas clearly detected in several nuclei in the differentiated myometrium. A similar transcriptional SRF-pathway fingerprint in FH-deficient and sporadic leiomyomas emphasizes the potential importance of this pathway in primary events leading to leiomyomatosis.