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«3. Medizinische Klinik und Poliklinik – Hämatologische Forschung Cks1 is a critical regulator of hematopoietic stem cell cycling, quiescence and ...»

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1.1. Cell cycle The cell cycle is an essential program, which cells necessarily undergo to reproduce and maintain a living organism. It involves a series of events in order to duplicate the cell DNA and to deliver copies of two identical daughter cells.

The cell phases are strongly controlled by certain proteins and their regulation is of major significance for the proper function of cell division and proliferation.

Failures in control of the cell cycle are crucial for the cell fate determination transformation and cancer [1].

1.1.1. Phases and checkpoints of the cell cycle Each cell is born at the end of the mitosis phase, a process which describes the cell division. The chromosomal DNA is replicated in the S phase (synthetic phase). The other two phases are gaps (G1 and G2) between mitosis and the S phase. The G1 phase, of various duration where the cell exerts its functions, is the interval between mitosis and S phase and comparatively short G2 phase is between the DNA replication and mitosis [2].

The transition between the different cell phases is controlled at specific checkpoints. These are biochemical pathways which modulate the progression through the cell cycle in response to external and internal signals. The restriction point in the G1 phase is a response to size and physiological state of the cell and the influence of the extracellular matrix. The DNA damage checkpoint monitors the integrity of the DNA. The metaphase checkpoint (also spindle assembly checkpoint) controls the attachment of the chromosomes to the mitotic spindle [3, 4].

A special compartment of the cell cycle is the G0 phase. A lot of cells with specific functions stay at the G0 phase and could be either dormant or actively engaged in protein synthesis and secretion. In response to certain stimuli G0 cells can enter the cell cycle [2]. The G1 phase is the longest and most variable cell phase, at which the cell is growing, preparing for divisions and undergoing the restriction checkpoint and the G1 DNA damage checkpoints [3, 4]. Both

INTRODUCTION

control points are defect in many cancer types, leading to deregulated division of the cells independent from external signals and existing DNA damage [1, 5].

Successful entry into the S phase is followed by replication of DNA, a complicated process, which is crucial for the cell’s survival. The replication of the large chromosomes of higher eukaryotes is initiated at many different sites along the chromosomal DNA, called origins of replication. As replication is initiated at each origin, components of the prereplication complex (formed in the G1 phase) are deactivated, preventing any region of the chromosome from replicating twice [2].

The following G2 phase is the transition into mitosis and comprises the G2 DNA damage checkpoint, an essential control of the replicated DNA. Defects at this checkpoint can lead to cancer and if the control is working properly, any kind of damage of the DNA leads to G2 delay [3, 4].

Mitosis is defined as the actual splitting of the cell into two daughter cells and consists of prophase, prometaphase, metaphase, anaphase, telophophase and cytokinesis. Mitosis involves a dramatic reorganization of the nucleus and the cytoplasm, controlled by a number of enzyme complexes, the regulation of which is essential for the correct completion of the division of the cell and the cell cycle [6].

1.1.2. Cell cycle control: Cyclin/CDK comlexes Precise control during all cell cycle phases and checkpoints is highly important for maintaining the physiological functions of a living organism. The main controlling proteins in the progression through the cell cycle are Cyclin/Cyclindependent kinase complexes and their inhibitors cyclin dependent kinse inhibitors [2].

Cyclin-dependent kinases (CDK) are enzymes acting on the transition point of the cell cycle and always need to form a complex with a regulatory subunit, a cyclin, in order to be active. The interaction of cyclin/CDK complexes serves to phosphorylate intracellular proteins, which are involved in the regulation of different cell cycle events. Assembly and disassembly of phase specific cyclin/Cdk-complexes regulates the progression through the cell cycle [7].

Tree kinds of D-type cyclins (D1, D2 and D3) form a complex and regulate the early G1 phase with one of the two CDK subunits CDK4 or CDK6. Activated

INTRODUCTION

CDK4 or CDK6 phosphorylate transcriptional repressors from the retinoblastoma (Rb) family (pRb, p103 and p107) releasing their inhibitory effect on E2F transcription factors [7-10]. Active E2F transcription factors trigger the expression of cell cycle genes like cyclin E and A. The E-type cyclins (E1 and E2) interact with CDK2 in the late G1 phase and are necessary for further Rb phosphorylation and activation of E2F regulated genes and for passing through the restriction point, initiating S Phase entry [7-9]. A or B-type cyclins in complex with CDK1 are required for transit through G2-M. A-type cyclins bind to CDK2 at the end of the S phase and to CDK1 at the beginning of G2, whereas B-type cyclins activate CDK1 during the end of the G2 phase and the transition to mitosis [9, 11, 12] (Fig. 1).

1.1.3. Cell cycle control: CDK inhibitors Correct functioning of the cell cycle machinery requires precise up- or down regulation of CDK activity. One of the strategies for negative regulation involves the binding of small inhibitory subunits of the CKI (cyclin-dependent kinase inhibitor) families (Fig. 1). CKI belong to either the INK4- or the CIP/KIP family [2].





Figure 1: Regulators of the cell cycle (Modified from Donovan and Slingerland, 2000 [13]).

INTRODUCTION

INK4 Family The INK4 family consists of p16Ink4a (p16), p15Ink4Bb (p15), p18Ink4c (p18) and p19Ink4d (p19), which bind CDK4 and CDK6 and inhibit their activation in complexes with D-type cyclins [8] and p19ARF, which is not a CKI and positively regulates the transcription factor p53 [14].

CIP/KIP Family The CIP/KIP family members p21Cip (p21), p27Kip1 (p27) and p57Kip2 (p57) can deactivate all of the CDK involved in cell cycle progression [8]. They display different affinity to the cyclin-CDK complexes, play different roles in cell cycle regulation and bind, in contrast to INK4 family members, to the whole cyclin/CDK complex [15-17]. The CKI from the CIP/KIP family inhibit mainly G1 cyclin/CDK complexes and cyclinB/CDK1 complexes [8, 18]. The CKI p21 acts also as inhibitor of DNA expression by repressing the proliferating cell nuclear antigen (PCNA) [19, 20]. CKI themselves are regulated upon external or internal signals. For example, the p21 promotor comprises a p53 binding site, so that p53 can activate the expression of the p21 gene causing a DNA damage induced cell cycle arrest in G1 or G2 [21, 22], whereas expression of p27 is mostly increased in the absence of external mitogen signals and at quiescence phases [23, 24]. The CKI p57 is specifically expressed in certain tissues during the embryonic development and in the adult organism [16, 25] and is the only CKI required in embryogenesis [26, 27].

Phenotypes of mice lacking the different CKI from the CIP/KIP family underline their role and importance in the regulation of cell reproduction. Knockouts for p27 exhibit multiple organ hyperplasia and increased body size [28]. Cells from p21-/- mice are disturbed at the G1 checkpoint and not capable to undergo a DNA-damage-induced cell cycle arrest [29]. And p57-/- embryos display hyperplasia in different organs and altered differentiation and proliferation [27].

1.2. Hematopoiesis The mammalian blood system consists of more than 10 different mature cell types, including erythrocytes, thrombocytes, T- and B lymphocytes, natural killer cells, granulocytes, monocytes and dendritic cells. Different kinds of blood cells are required for different functions in the organism. The red blood cells

INTRODUCTION

(erythrocytes) are responsible for oxygen transport, the white blood cells (leukocytes) are important for the immune response and the platelets (thrombocytes) are involved in blood clotting. The strictly regulated process of blood cells formation is called hematopoiesis. All mature blood cell types arise from a small population of multipotent hematopoietic stem cells (HSC) which reside in the bone marrow, persist for a life-time and form the beginning of a hierarchical organization [30].

1.2.1. Hematopoietic stem cells When blood cells are lost or turned over, the dormant HSC are initiated to divide. Toward internal and external signals, the multipotent HSC can differentiate and develop to hematopoietic progenitor cells (HPC), which on their side, differentiate further, become lineage restricted and give rise to all mature blood cells [31, 32]. Since HSC replenish the blood system throughout lifetime, they need to self-renew in order to maintain their stem cell character. Selfrenewal is together with quiescence the most important characteristic of HSC and is experimentally defined as the capacity for long term reconstitution of all blood lineages upon transplantation into a recipient [33].

Developmental origin of HSC Before reaching their quiescent state in the adult bone marrow, HSC pass through an active cell cycling and proliferation phase during embryogenesis in order to generate the blood system [32, 34]. Primitive hematopoiesis in the mice embryo involve rapid production of red blood cells for oxygen transport and little HSC activity and takes place in the yolk sac at embryonic day E7,5 [35, 36].

The so called “definitive” hematopoiesis, the generation of all blood lineages, is a longsome process and occurs in different regions of the embryo. Definitive HSC could be isolated from the aorta-gonad-mesonephros (AGM) region and the placenta by E8,5 and from the yolk sac by E10 [37-39]. Later, HSC expand in the fetal liver till the end of the embryonic life [36]. By E17,5 and through the first two weeks of postnatal life, HSC leave the liver and colonize the bones [32, 40].

INTRODUCTION

The hematopoietic hierarchy During years of research, using cell surface marker phenotype, scientists identified and isolated distinct subpopulations of blood cells. Specific assays delivered information about function, developmental stage and self-renewal, respectively differentiation ability of the different blood cell types. The analysis suggested a hierarchical organization during hematopoietic development with progressive restriction of self-renewal capacity at each further hierarchical step (Fig. 2 and [41]).

Long-term HSC (LT-HSC) are the most primitive compartment in the hierarchy (Fig. 2). LT-HSC can undergo asymmetric divisions and either self-renew into identical copies of themselves and maintain their stem cell qualities, or differentiate into short term HSC (ST-HSC) [31, 42]. ST-HSC have a shorter life span and lower self-renewal capacity and can differentiate into multipotent progenitor cells (MPP). MPP possess very low to no self-renewal potential and are capable of differentiation and commitment into either lymphoid or myeloid lineage restricted progenitors: common lymphoid progenitors (CLP) and common myeloid progenitors (CMP). CLP and CMP give rise to all of the mature blood cell types [31, 42]. T, B lymphocytes, natural killer cells and the antigen presenting dendritic cells develop from CLP. The CMP commit either to GMP (granulocyte monocyte committed progenitors) or to MEP (megakaryocyte erythrocyte progenitors). The GMP develop to granulocytes, monocytes and dendritic cells and the MEP give rise to erythrocytes and platelets [31, 42].

Surface marker in HSC/HPC The different blood cell types can be identified on the basis of phenotypic surface markers using flow cytometry. All HSC are negative for lineage markers (Lin-) and express the stem cell antigen 1 (Sca1 or Ly6A/E) and the receptor for stem cell factor (c-Kit or CD117) on their surface (Fig. 1). Therefore HSC are also called LSK (Lin-Sca1+cKit+) [31, 43, 44]. During the last decade, further surface markers were established and the definition of LT- and ST-HSC has been defined more and more precisely.

LT-HSC are enriched in the CD34-/low and receptor tyrosine kinase, (Flk2) negative LSK fraction, while ST-HSC can be found in the CD34+ Flk2+ LSK subset [44, 45]. Although low expression of Thy1.1 is a marker in all LSK cells

INTRODUCTION

[42], the loss of Thy1.1 surface protein together with gain of Flk2 is shown to mark the loss of self-renewal potential in HSC [45]. LT-HSC can be distinguished from ST-HSC also through expression of the SLAM-family markers CD150 and CD48, whereas the early LT-HSC are negative for CD48 or CD34 and positive for CD150 [46-48].

The further differentiation state in the hierarchy, the MPP, is also defined as Linand c-Kit+, but the cells express either low or no Sca1 on their surface (Sca1 Sca1lo/-) and interleukin 7 receptor α (IL7Rα) is a typical marker used to differentiate the myeoloid and lymphoid progenitor lineages, as CLP are shown to be Thy1.1- and IL7Rα+ [49]. The IL7Rα- fraction of MPP includes the three kinds of myeloid progenitors which on their side are being distinguished by the expression of CD34 and Fcγ Receptor (CD16/32). CMP are CD34+ CD16/23-, GMP are CD34+ CD16/32hi and MEP are CD34- CD16/32lo [42, 50].

Figure 2: Hematopoietical tree in mice (Modified from Shizuru et. Al., 2005 [42]).

1.2.2. Regulatory signals in HSC The production of close to 1012 mature blood cells per day from the HSC/HPC pool requires a tightly regulated adjustment to intrinsic and environmental stimuli [30, 51, 52]. Regulation of the cell cycle plays a key role at each step of

INTRODUCTION

hematopoiesis and also serves as a checkpoint towards uncontrolled cell proliferation that might lead to blood malignancies [32].

HSC reside in a specific microenvironment in the bone marrow, the so called niche, which is highly important for the regulation of HSC behavior through extrinsic signals. The hematopoietic stem cell niche is a complex microenvironment, consisting of different cell types and extracellular elements [53, 54]. Molecular cross-talk between HSC and the cells in the niche environment is carried out through a direct cell contact, growth factors and cytokines or components of the extracellular matrix and is of major importance for the developmental fate of the HSC [53, 55].



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