Overlapping roles for homeodomain-interacting protein kinases hipk1 and hipk2 in the mediation of cell growth in response to morphogenetic and genotoxic signals.
Homeodomain-interacting protein kinase 1 (Hipk1), 2, and 3 genes encode evolutionarily conserved nuclear serine/threonine kinases, which were originally identified as interacting with homeodomain-containing proteins. Hipks have been repeatedly identified as interactors for a vast range of functional proteins, including not only transcriptional regulators and chromatin modifiers but also cytoplasmic signal transducers, transmembrane proteins, and the E2 component of SUMO ligase. Gain-of-function experiments using cultured cells indicate growth regulatory roles for Hipks on receipt of morphogenetic and genotoxic signals. However, Hipk1 and Hipk2 singly deficient mice were grossly normal, and this is expected to be due to a functional redundancy between Hipk1 and Hipk2. Therefore, we addressed the physiological roles of Hipk family proteins by using Hipk1 Hipk2 double mutants. Hipk1 Hipk2 double homozygotes are progressively lost between 9.5 and 12.5 days postcoitus and frequently fail to close the anterior neuropore and exhibit exencephaly. This is most likely due to defective proliferation in the neural fold and underlying paraxial mesoderm, particularly in the ventral region, which may be attributed to decreased responsiveness to Sonic hedgehog signals. The present study indicated the overlapping roles for Hipk1 and Hipk2 in mediating cell proliferation and apoptosis in response to morphogenetic and genotoxic signals during mouse development.
RIKEN Research Center for Allergy and Immunology, 1-7-22 Suehiro, Tsurumi-ku, Yokohama 230-0045, Japan.
Kyoichi
K
Isono
Kazumi
K
Nemoto
Yuanyuan
Y
Li
Yuki
Y
Takada
Rie
R
Suzuki
Motoya
M
Katsuki
Akira
A
Nakagawara
Haruhiko
H
Koseki
D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002453:Cell Cycle; D048708:Cell Growth Processes / Q000187:drug effects; D049109:Cell Proliferation; D002478:Cells, Cultured; D020964:Embryo Loss / Q000378:metabolism / Q000473:pathology; D047108:Embryonic Development / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D053823:Hedgehog Proteins; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006720:Homozygote; D008648:Mesoderm / Q000166:cytology; D051379:Mice; D009024:Morphogenesis / Q000187:drug effects; D009153:Mutagens / Q000378:metabolism* / Q000494:pharmacology; D009436:Neural Tube Defects / Q000473:pathology; D009474:Neurons / Q000166:cytology; D051761:Paired Box Transcription Factors / Q000378:metabolism; D011485:Protein Binding; D011494:Protein Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport; D015398:Signal Transduction / Q000187:drug effects; D015534:Trans-Activators / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D002352:Carrier Proteins; D053823:Hedgehog Proteins; D018398:Homeodomain Proteins; D009153:Mutagens; D051761:Paired Box Transcription Factors; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; C070835:PAX1 transcription factor; D011494:Protein Kinases; C492003:Hipk2 protein, mouse; C115113:Hipk1 protein, mouse; D017346:Protein Serine-Threonine Kinases