Parafibromin, a component of the human PAF complex, regulates growth factors and is required for embryonic development and survival in adult mice.
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.
Wang
Pengfei
P
Van Andel Research Institute, 333 Bostwick Avenue, N.E., Grand Rapids, MI 49503, USA.
Bowl
Michael R
MR
Bender
Stephanie
S
Peng
Jun
J
Farber
Leslie
L
Chen
Jindong
J
Ali
Asif
A
Zhang
Zhongfa
Z
Alberts
Arthur S
AS
Thakker
Rajesh V
RV
Shilatifard
Ali
A
Williams
Bart O
BO
Teh
Bin Tean
BT
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002100:Cachexia / Q000378:metabolism / Q000473:pathology; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D020964:Embryo Loss / Q000235:genetics; D005347:Fibroblasts / Q000378:metabolism; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis* / Q000235:genetics; D007668:Kidney / Q000196:embryology* / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000196:embryology* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D012469:Salivary Glands / Q000196:embryology* / Q000378:metabolism / Q000473:pathology; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000502:physiology*
C454900:CDC73 protein, human; C529591:HRPT2 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D025521:Tumor Suppressor Proteins