title: PDK1 regulates VDJ recombination, cell-cycle exit and survival during B-cell development.
abstract: Phosphoinositide-dependent kinase-1 (PDK1) controls the activation of a subset of AGC kinases. Using a conditional knockout of PDK1 in haematopoietic cells, we demonstrate that PDK1 is essential for B cell development. B-cell progenitors lacking PDK1 arrested at the transition of pro-B to pre-B cells, due to a cell autonomous defect. Loss of PDK1 decreased the expression of the IgH chain in pro-B cells due to impaired recombination of the IgH distal variable segments, a process coordinated by the transcription factor Pax5. The expression of Pax5 in pre-B cells was decreased in PDK1 knockouts, which correlated with reduced expression of the Pax5 target genes IRF4, IRF8 and Aiolos. As a result, Ccnd3 is upregulated in PDK1 knockout pre-B cells and they have an impaired ability to undergo cell-cycle arrest, a necessary event for Ig light chain rearrangement. Instead, these cells underwent apoptosis that correlated with diminished expression of the pro-survival gene Bcl2A1. Reintroduction of both Pax5 and Bcl2A1 together into PDK1 knockout pro-B cells restored their ability to differentiate in vitro into mature B cells.
authors: MRC Protein Phosphorylation Unit, Sir James Black Centre, College of Life Sciences, University of Dundee, Dundee, UK. ramkumar.venigalla@babraham.ac.uk
authors: Ram K C
authors: RK
authors: Venigalla
authors: Victoria A
authors: VA
authors: McGuire
authors: Rosemary
authors: R
authors: Clarke
authors: Janet C
authors: JC
authors: Patterson-Kane
authors: Ayaz
authors: A
authors: Najafov
authors: Rachel
authors: R
authors: Toth
authors: Pierre C
authors: PC
authors: McCarthy
authors: Frederick
authors: F
authors: Simeons
authors: Laste
authors: L
authors: Stojanovski
authors: J Simon C
authors: JS
authors: Arthur
mesh_terms: D064413:3-Phosphoinositide-Dependent Protein Kinases; D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D059447:Cell Cycle Checkpoints / Q000502:physiology*; D056743:Cyclin D3 / Q000235:genetics / Q000378:metabolism; D055785:Gene Knockdown Techniques; D051740:Ikaros Transcription Factor; D007143:Immunoglobulin Heavy Chains / Q000096:biosynthesis* / Q000235:genetics; D007147:Immunoglobulin Light Chains / Q000096:biosynthesis* / Q000235:genetics; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D015778:Minor Histocompatibility Antigens; D051757:PAX5 Transcription Factor / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000502:physiology; D060152:V(D)J Recombination / Q000502:physiology*; D000099185:Interferon Regulatory Factor-8; D000099218:Interferon Regulatory Factor-4
chemical_list: D064413:3-Phosphoinositide-Dependent Protein Kinases; D056743:Cyclin D3; D051740:Ikaros Transcription Factor; D007143:Immunoglobulin Heavy Chains; D007147:Immunoglobulin Light Chains; D050835:Interferon Regulatory Factors; D015778:Minor Histocompatibility Antigens; D051757:PAX5 Transcription Factor; D017346:Protein Serine-Threonine Kinases; D019253:Proto-Oncogene Proteins c-bcl-2; D015534:Trans-Activators; D000099185:Interferon Regulatory Factor-8; D000099218:Interferon Regulatory Factor-4; C096816:BCL2-related protein A1; C534697:Ccnd3 protein, mouse; C491396:Ikzf3 protein, mouse; C497282:Pax5 protein, mouse; C578564:Pdpk1 protein, mouse