title: Multiple apoptotic defects in hematopoietic cells from mice lacking lipocalin 24p3.
abstract: The lipocalin mouse 24p3 has been implicated in diverse physiological processes, including apoptosis, iron trafficking, development and innate immunity. Studies from our laboratory as well as others demonstrated the proapoptotic activity of 24p3 in a variety of cultured models. However, a general role for the lipocalin 24p3 in the hematopoietic system has not been tested in vivo. To study the role of 24p3, we derived 24p3 null mice and back-crossed them onto C57BL/6 and 129/SVE backgrounds. Homozygous 24p3(-/-) mice developed a progressive accumulation of lymphoid, myeloid, and erythroid cells, which was not due to enhanced hematopoiesis because competitive repopulation and recovery from myelosuppression were the same as for wild type. Instead, apoptotic defects were unique to many mature hematopoietic cell types, including neutrophils, cytokine-dependent mast cells, thymocytes, and erythroid cells. Thymocytes isolated from 24p3 null mice also displayed resistance to apoptosis-induced by dexamethasone. Bim response to various apoptotic stimuli was attenuated in 24p3(-/-) cells, thus explaining their resistance to the ensuing cell death. The results of these studies, in conjunction with those of previous studies, reveal 24p3 as a regulator of the hematopoietic compartment with important roles in normal physiology and disease progression. Interestingly, these functions are limited to relatively mature blood cell compartments.
authors.affiliation: Case Comprehensive Cancer Center and Department of Pathology, Case Western Reserve University, Cleveland, Ohio 44106, USA.
authors.forename: Zhuoming
authors.initials: Z
authors.lastname: Liu
authors.forename: Amy
authors.initials: A
authors.lastname: Yang
authors.forename: Zhengqi
authors.initials: Z
authors.lastname: Wang
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Bunting
authors.forename: Gangarao
authors.initials: G
authors.lastname: Davuluri
authors.forename: Michael R
authors.initials: MR
authors.lastname: Green
authors.forename: Laxminarayana R
authors.initials: LR
authors.lastname: Devireddy
mesh_terms: D000209:Acute-Phase Proteins / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D001773:Blood Cells / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology; D006410:Hematopoiesis / Q000187:drug effects / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D000071068:Lipocalin-2; D054834:Lipocalins / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D000209:Acute-Phase Proteins; D000893:Anti-Inflammatory Agents; D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D000071068:Lipocalin-2; D054834:Lipocalins; D008565:Membrane Proteins; D015513:Oncogene Proteins; D011518:Proto-Oncogene Proteins; C071332:Lcn2 protein, mouse; D003907:Dexamethasone