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Mol. Cell. Biol. doi:10.1128/MCB.00654-07
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Parafibromin, a component of the human PAF complex, regulates growth factors and is required for embryonic development and survival in adult mice

Laboratory of Cancer Genetics; Laboratory of Cell Structure and Signal Integration; Laboratory of Cell Signaling and Cancinogenesis; Van Andel Research Institute,333 Bostwick Ave., NE, Grand Rapids, Michigan 49503; Stowers Institute for Medical Research, 1000 E 50^th Street, Kansas City, MO 64110; Academic Endocrine Unit, Nuffield Department of Clinical Medicine, University of Oxford, OCDEM, Churchill Hospital, Oxford, OX3 7LJ, UK

^* To whom correspondence should be addressed. Email: rajesh.thakker{at}ndm.ox.ac.uk. Bin.Teh{at}vai.org.

	Abstract

Parafibromin, a transcription factor associated with the PAF complex, is encoded by the HRPT2 gene, mutations of which cause the hyperparathyroidism–jaw tumor syndrome (OMIM145001). To elucidate the function of parafibromin, we generated conventional and conditional Hrpt2 knockout mice and found that Hrpt2^-/- mice were embryonic lethal by E6.5. Controlled deletion of Hrpt2 after E8.5, resulted in apoptosis and growth retardation. Deletion of Hrpt2 in adult mice lead to severe cachexia and death within 20 days. To explore the mechanism underlying the embryonic lethality and death of adult mice, mouse embryonic fibroblasts (MEFs) were cultured and Hrpt2 deleted in vitro. Hrpt2^-/- MEFs underwent apoptosis whilst Hrpt2^+/+ and Hrpt2^+/- MEFs grew normally. To study the mechanism of this apoptosis, Hrpt2^+/+ and Hrpt2^-/- MEFs were used in cDNA microarray, semiquantative RT-PCR, and chromatin immunoprecipitation assays to identify genes regulated by parafibromin. These revealed that Hrpt2 expression and the parafibromin/PAF complex directly regulate genes involved in cell growth and survival, that included H19, Igf1, Igf2, Igfbp4, Hmga1, Hmga2 and Hmgcs2. Thus, our results show that expression of Hrpt2 and parafibromin, is pivotal in mammalian development and survival in adults, and that these functions are likely mediated by the transcriptional regulation of growth factors.