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Molecular and Cellular Biology, May 2008, p. 2930-2940, Vol. 28, No. 9
0270-7306/08/$08.00+0     doi:10.1128/MCB.00654-07
Copyright © 2008, American Society for Microbiology. 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{triangledown} ,{dagger}

Pengfei Wang,1,{ddagger} Michael R. Bowl,2 Stephanie Bender,1 Jun Peng,3,§ Leslie Farber,1 Jindong Chen,1 Asif Ali,2 ZhongFa Zhang,1 Arthur S. Alberts,3 Rajesh V. Thakker,2* Ali Shilatifard,5 Bart O. Williams,4 and Bin Tean Teh1*

Laboratory of Cancer Genetics,1 Laboratory of Cell Structure and Signal Integration,3 Laboratory of Cell Signaling and Cancinogenesis, Van Andel Research Institute, 333 Bostwick Ave., NE, Grand Rapids, Michigan 49503,4 Stowers Institute for Medical Research, 1000 E. 50th Street, Kansas City, Missouri 64110,5 Academic Endocrine Unit, Nuffield Department of Clinical Medicine, University of Oxford, OCDEM, Churchill Hospital, Oxford OX3 7LJ, United Kingdom2

Received 13 April 2007/ Returned for modification 15 June 2007/ Accepted 7 January 2008

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 embryonic day 6.5 (E6.5). Controlled deletion of Hrpt2 after E8.5 resulted in apoptosis and growth retardation. Deletion of Hrpt2 in adult mice led 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 was deleted in vitro. Hrpt2–/– MEFs underwent apoptosis, while Hrpt2+/+ and Hrpt2+/– MEFs grew normally. To study the mechanism of this apoptosis, Hrpt2+/+ and Hrpt2–/– MEFs were used in cDNA microarray, semiquantitative reverse transcription-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, including 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.

* Corresponding author. Mailing address for Bin Tean Teh: Van Andel Research Institute, 333 Bostwick Avenue, N.E., Grand Rapids, MI 49503. Phone: (616) 234-5296. Fax: (616) 234-5297. E-mail: Bin.Teh{at}vai.org. Mailing address for Rajesh V. Thakker: Academic Endocrine Unit, Nuffield Department of Clinical Medicine, University of Oxford, OCDEM, Churchill Hospital, Oxford OX3 7LJ, United Kingdom. Phone: 865-857501. Fax: 865-857502. E-mail: rajesh.thakker{at}ndm.ox.ac.uk

{triangledown} Published ahead of print on 22 January 2008.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

{ddagger} Present address: Stowers Institute for Medical Research, 1000 E. 50th Street, Kansas City, MO 64110.

§ Present address: Cleveland Clinic, Genomic Medicine Institute, 9500 Euclid Avenue, Cleveland, OH 44195.

Molecular and Cellular Biology, May 2008, p. 2930-2940, Vol. 28, No. 9
0270-7306/08/$08.00+0     doi:10.1128/MCB.00654-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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