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1471-2164-10-261.Pdf BMC Genomics BioMed Central Research article Open Access Molecular signature of cell cycle exit induced in human T lymphoblasts by IL-2 withdrawal Magdalena Chechlinska*1, Jan Konrad Siwicki1, Monika Gos2, Malgorzata Oczko-Wojciechowska3, Michal Jarzab4, Aleksandra Pfeifer3, Barbara Jarzab3 and Jan Steffen1 Address: 1Department of Immunology, Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, Warsaw, Poland, 2Department of Cell Biology, Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, Warsaw, Poland, 3Department of Nuclear Medicine and Endocrine Oncology, Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, Gliwice, Poland and 4Department of Tumor Biology and Clinical Oncology, Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, Gliwice, Poland Email: Magdalena Chechlinska* - [email protected]; Jan Konrad Siwicki - [email protected]; Monika Gos - [email protected]; Malgorzata Oczko-Wojciechowska - [email protected]; Michal Jarzab - [email protected]; Aleksandra Pfeifer - [email protected]; Barbara Jarzab - [email protected]; Jan Steffen - [email protected] * Corresponding author Published: 8 June 2009 Received: 20 February 2009 Accepted: 8 June 2009 BMC Genomics 2009, 10:261 doi:10.1186/1471-2164-10-261 This article is available from: http://www.biomedcentral.com/1471-2164/10/261 © 2009 Chechlinska et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract Background: The molecular mechanisms of cell cycle exit are poorly understood. Studies on lymphocytes at cell cycle exit after growth factor deprivation have predominantly focused on the initiation of apoptosis. We aimed to study gene expression profile of primary and immortalised IL- 2-dependent human T cells forced to exit the cell cycle by growth factor withdrawal, before apoptosis could be evidenced. Results: By the Affymetrix microarrays HG-U133 2.0 Plus, 53 genes were distinguished as differentially expressed before and soon after IL-2 deprivation. Among those, PIM1, BCL2, IL-8, HBEGF, DUSP6, OSM, CISH, SOCS2, SOCS3, LIF and IL13 were down-regulated and RPS24, SQSTM1, TMEM1, LRRC8D, ECOP, YY1AP1, C1orf63, ASAH1, SLC25A46 and MIA3 were up-regulated. Genes linked to transcription, cell cycle, cell growth, proliferation and differentiation, cell adhesion, and immune functions were found to be overrepresented within the set of the differentially expressed genes. Conclusion: Cell cycle exit of the growth factor-deprived T lymphocytes is characterised by a signature of differentially expressed genes. A coordinate repression of a set of genes known to be induced during T cell activation is observed. However, growth arrest following exit from the cell cycle is actively controlled by several up-regulated genes that enforce the non-dividing state. The identification of genes involved in cell cycle exit and quiescence provides new hints for further studies on the molecular mechanisms regulating the non-dividing state of a cell, the mechanisms closely related to cancer development and to many biological processes. Page 1 of 15 (page number not for citation purposes) BMC Genomics 2009, 10:261 http://www.biomedcentral.com/1471-2164/10/261 Background tor withdrawal, and their gene expression profiles were Cell growth, proliferation and arrest mechanisms are cru- examined. cial for development and homeostasis. Extensive studies have examined the mechanisms of cell activation and cell Results and discussion cycle progression, which involve sequential effects of To gain new insights into cell cycle exit of T lymphocytes, growth factors and their receptors and activation of intra- we performed gene expression profiling in human IL-2- cellular signal transduction pathways, transcription fac- dependent T lymphoblasts deprived of the growth factor. tors, cyclins and cyclin-dependent kinases [1]. Studies on Following IL-2 withdrawal, IL-2-dependent, proliferating lymphocytes withdrawn from the cell cycle have focused T lymphoblasts cease to divide and undergo apoptosis on the initiation of apoptosis following growth factor [19]. Therefore, transcription profiles of T cells were ana- deprivation [2-8] or on the cell-to-cell contact mecha- lysed soon after IL-2 withdrawal (8 hours), before apop- nisms that prevent cells from apopotosis [9-11]. Still, the totic changes could be observed. In addition, to minimize molecular mechanisms of cell cycle exit remain poorly effects associated with the heterogeneity of primary T cell understood. With the lack of mitogenic signals, and in populations, we also studied clonal populations of response to antiproliferative signals such as mitogen with- immortalised IL-2-dependent T lymphoblasts and looked drawal, growth factor starvation, contact inhibition or for the common changes in the two cellular models. We DNA damage, a proliferating cell arrests to become quies- believe that this approach also limited the "non-specific" cent (a reversible, nondividing state) or senescent, or to gene expression changes in the primary IL-2-deprived T undergo apoptotic death. Most somatic cells in an adult lymphoblasts, i.e. not related to IL-2 withdrawal, but body remain in a postmitotic G0 phase. However, during rather to the possible paracrine signalling in polyclonal tissue regeneration and repair, wound healing and populations by other cytokines characterised by a redun- immune response, cells re-enter the cell cycle and subse- dant activity. quently withdraw from proliferation. Five cell lines were subjected to IL-2 deprivation and Studies in lymphocytes and fibroblasts have shown that microarray analysis, three primary, IL-2-dependent T lym- resting cells are not in a passive state resulting simply from phoblast lines derived from three different donors the lack of stimulation. Pajalunga et al. [12] summarized (denoted "6", "43" and "j") and two immortalised T cell cell cycle exit as "a shift in the balance between positive lines (denoted line 5 and S9), examined in three biologi- and negative regulators of proliferation in favour of the cal replicates each. Altogether, 18 microarray hybridisa- latter". Indeed, resting cells were found to express sets of tions were performed. up-regulated and down-regulated genes that maintained an active state of non-division [1,12,13,15,16]. A group of In the first step, unsupervised Principal Component Anal- genes required for cell cycle exit and the maintenance of ysis was performed to assess the reliability of the experi- cell quiescence in human fibroblasts following serum ments. Biological replicates were shown to cluster deprivation has been recently identified [17]. Compara- together. The gene expression profile of all the analysed tive studies of transcriptional profiles of resting and stim- cell lines was shown to be affected by IL-2 withdrawal, but ulated lymphocytes [1,18] have shown that T lymphocyte the major variability of the gene expression profile in the quiescence is actively maintained by products of a set of analysed dataset was found between primary and immor- genes, including TOB and KLF (LKLF, GKLF and BKLF) talised cell lines (unpublished data). Differences between and FOXO families of transcription factors. Other candi- primary and immortalised cells were much greater than date genes involved in lymphocyte quiescence, including those resulting from IL-2 withdrawal. Therefore, our anal- TSC-22 and Dyrk1, have been identified in a mouse model ysis was carried out in a block design, and changes in gene among genes highly expressed in resting lymphocytes and expression following IL-2 withdrawal were assessed sepa- down-regulated after T or B cell activation [1]. rately in primary and immortalised cell lines. By means of the parametric non-corrected t-test we selected 158 differ- The present study on a human T cell model may provide entially expressed genes at p < 0.001 (see Additional File new insights into the molecular changes involved in cell 1: Table A1 for genes differentiating between samples proliferation control, cell cycle exit and cellular quies- before and after IL-2 withdrawal, selected by a non-paired cence. Cellular quiescence represents an important safe- analysis). The probability of a random selection of such a guard against tumorigenesis; therefore the identification number of genes was low (0.03 in a global test) which of quiescence-controlling genes and a better understand- confirmed the reliability of the observed differences. A ing of the relevant molecular pathways may open new false discovery rate for the selected genes ranged from possibilities in cancer diagnosis and treatment. Thus, in 0.003 to 0.12. The hierarchical clustering of the 158 differ- our study, proliferating interleukin (IL)-2-dependent entially expressed probe-sets obtained in this analysis human T cells were forced to exit cell cycle by growth fac- resulted in an ideal discrimination between the samples Page 2 of 15 (page number not for citation purposes) BMC Genomics 2009, 10:261 http://www.biomedcentral.com/1471-2164/10/261 before and after IL-2 withdrawal, with a rather uniform the role of Lck in transient T cell unresponsiveness, medi- pattern of expression (Figure 1). ated by a selective IL-2 deficiency. Thus, SQSTM1 may play an important
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