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      Roles of p53 in Various Biological Aspects of Hematopoietic Stem Cells

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          Abstract

          Hematopoietic stem cells (HSCs) have the capacity to self-renew as well as to differentiate into all blood cell types, and they can reconstitute hematopoiesis in recipients with bone marrow ablation. In addition, transplantation therapy using HSCs is widely performed for the treatment of various incurable diseases such as hematopoietic malignancies and congenital immunodeficiency disorders. For the safe and successful transplantation of HSCs, their genetic and epigenetic integrities need to be maintained properly. Therefore, understanding the molecular mechanisms that respond to various cellular stresses in HSCs is important. The tumor suppressor protein, p53, has been shown to play critical roles in maintenance of “cell integrity” under stress conditions by controlling its target genes that regulate cell cycle arrest, apoptosis, senescence, DNA repair, or changes in metabolism. In this paper, we summarize recent reports that describe various biological functions of HSCs and discuss the roles of p53 associated with them.

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          Most cited references90

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          Extension of life-span by introduction of telomerase into normal human cells.

          Normal human cells undergo a finite number of cell divisions and ultimately enter a nondividing state called replicative senescence. It has been proposed that telomere shortening is the molecular clock that triggers senescence. To test this hypothesis, two telomerase-negative normal human cell types, retinal pigment epithelial cells and foreskin fibroblasts, were transfected with vectors encoding the human telomerase catalytic subunit. In contrast to telomerase-negative control clones, which exhibited telomere shortening and senescence, telomerase-expressing clones had elongated telomeres, divided vigorously, and showed reduced straining for beta-galactosidase, a biomarker for senescence. Notably, the telomerase-expressing clones have a normal karyotype and have already exceeded their normal life-span by at least 20 doublings, thus establishing a causal relationship between telomere shortening and in vitro cellular senescence. The ability to maintain normal human cells in a phenotypically youthful state could have important applications in research and medicine.
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            CDK inhibitors: positive and negative regulators of G1-phase progression.

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              Requirement for p53 and p21 to sustain G2 arrest after DNA damage.

              After DNA damage, many cells appear to enter a sustained arrest in the G2 phase of the cell cycle. It is shown here that this arrest could be sustained only when p53 was present in the cell and capable of transcriptionally activating the cyclin-dependent kinase inhibitor p21. After disruption of either the p53 or the p21 gene, gamma radiated cells progressed into mitosis and exhibited a G2 DNA content only because of a failure of cytokinesis. Thus, p53 and p21 appear to be essential for maintaining the G2 checkpoint in human cells.
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                Author and article information

                Journal
                J Biomed Biotechnol
                J. Biomed. Biotechnol
                JBB
                Journal of Biomedicine and Biotechnology
                Hindawi Publishing Corporation
                1110-7243
                1110-7251
                2012
                20 June 2012
                : 2012
                : 903435
                Affiliations
                1Division of Molecular and Clinical Genetics, Medical Institute of Bioregulation, Kyushu University, 3-1-1, Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
                2Department of Advanced Molecular and Cell Therapy, Kyushu University Hospital, 3-1-1, Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
                Author notes

                Academic Editor: Masamitsu Yamaguchi

                Article
                10.1155/2012/903435
                3388322
                22778557
                af0bdc4b-a564-4693-bdbf-731d5205a9aa
                Copyright © 2012 Takenobu Nii et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 22 March 2012
                : 14 May 2012
                Categories
                Review Article

                Molecular medicine
                Molecular medicine

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