Roles of HIPK1 and HIPK2 in AML1- and p300-dependent transcription, hematopoiesis and blood vessel formation.
Histone acetyltransferases (HATs) p300 and CREB-binding protein (CBP) function as co-activators for a variety of sequence-specific transcription factors, including AML1. Here, we report that homeodomain-interacting protein kinase-2 (HIPK2) forms a complex with AML1 and p300, and phosphorylates both AML1 and p300 to stimulate transcription activation as well as HAT activities. Phosphorylation of p300 is triggered by phosphorylated AML1 as well as by PU.1, c-MYB, c-JUN and c-FOS, and is inhibited by dominant-negative HIPK2. Phosphorylation of p300 and AML1 is impaired in Hipk1/2 double-deficient mouse embryos. Double-deficient mice exhibit defects in primitive/definitive hematopoiesis, vasculogenesis, angiogenesis and neural tube closure. These phenotypes are in part similar to those observed in p300- and CBP-deficient mice. HIPK2 also phosphorylates another co-activator, MOZ, in an AML1-dependent manner. We discuss a possible mechanism by which transcription factors could regulate local histone acetylation and transcription of their target genes.
Aikawa
Yukiko
Y
Molecular Oncology Division, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan.
Nguyen
Lan Anh
LA
Isono
Kyoichi
K
Takakura
Nobuyuki
N
Tagata
Yusuke
Y
Schmitz
M Lienhard
ML
Koseki
Haruhiko
H
Kitabayashi
Issay
I
D000107:Acetylation; D000595:Amino Acid Sequence; D000818:Animals; D001808:Blood Vessels / Q000196:embryology*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D004789:Enzyme Activation; D006410:Hematopoiesis; D051548:Histone Acetyltransferases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009389:Neovascularization, Pathologic / Q000235:genetics; D010766:Phosphorylation; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D020598:Proto-Oncogene Proteins c-myb / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D050880:p300-CBP Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000099232:Proto-Oncogene Protein Spi-1; D000099224:p300-CBP-Associated Factor
D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D050676:Core Binding Factor Alpha 2 Subunit; D051548:Histone Acetyltransferases; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D020598:Proto-Oncogene Proteins c-myb; D015534:Trans-Activators; D014157:Transcription Factors; D050880:p300-CBP Transcription Factors; D000099232:Proto-Oncogene Protein Spi-1; D000099224:p300-CBP-Associated Factor; C493726:Runx1 protein, mouse; C492003:Hipk2 protein, mouse; C115113:Hipk1 protein, mouse