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Mature red cells

► FIGURE 14-7 Role of erythropoietin in formation of red blood cells (erythrocytes). Erythroid progenitor cells, called colony-forming units erythroid (CFU-E), are derived from hematopoietic stem cells, which also give rise to progenitors of other blood cell types. In the absence of erythropoietin (Epo), CFU-E cells undergo apoptosis. Binding of erythropoietin to its receptors on a CFU-E induces transcription of several genes whose encoded proteins prevent programmed cell death (apoptosis), allowing the cell to survive and undergo a program of three to five terminal cell divisions. Epo stimulation also induces expression of erythrocyte-specific proteins such as the globins, which form hemoglobin, and the membrane proteins glycophorin and anion-exchange protein. The Epo receptor and other membrane proteins are lost from these cells as they undergo differentiation. If CFU-E cells are cultured with erythropoietin in a semisolid medium (e.g., containing methylcellulose), daughter cells cannot move away, and thus each CFU-E produces a colony of 30-100 erythroid cells, hence its name. [See M. Socolovsky et al., 2001, Blood 98:3261.]

lowing virus infection. The secreted interferons act on nearby cells to induce enzymes that render these cells more resistant to virus infection.

Many cytokines induce formation of important types of blood cells. For instance, granulocyte colony stimulating factor (G-CSF) induces a particular type of progenitor cell in the bone marrow to divide several times and then differentiate into granulocytes, the type of white blood cell that inactivates bacteria and other pathogens. Because many cancer therapies reduce granulo-cyte formation by the body, G-CSF often is administered to patients to stimulate proliferation and differentiation of granulocyte progenitor cells, thus restoring the normal level of granulocytes in the blood. Thrombopoietin, a "cousin" of G-CSF, similarly acts on megakaryocyte progenitors to divide and differentiate into megakaryocytes. These then fragment into the cell pieces called platelets, which are critical for blood clotting. I

Another related cytokine, erythropoietin (Epo), triggers production of red blood cells by inducing the proliferation and differentiation of erythroid progenitor cells in the bone marrow (Figure 14-7). Erythropoietin is synthesized by kidney cells that monitor the concentration of oxygen in the blood. A drop in blood oxygen signifies a lower than optimal level of erythrocytes (red blood cells), whose major function is to transport oxygen complexed to hemoglobin. By means of the oxygen-sensitive transcription factor HIF-1a, the kidney cells respond to low oxygen by synthesizing more ery-thropoietin and secreting it into the blood (see Figure 15-9). As the level of erythropoietin rises, more and more erythroid progenitors are saved from death, allowing each to produce «50 or so red blood cells in a period of only two days. In this way, the body can respond to the loss of blood by accelerating the production of red blood cells.

All Cytokines and Their Receptors Have Similar Structures and Activate Similar Signaling Pathways

Strikingly, all cytokines have a similar tertiary structure, consisting of four long conserved a helices folded together in a specific orientation. Similarly, the structures of all cytokine receptors are quite similar, with their extracellular domains constructed of two subdomains, each of which contains seven conserved p strands folded together in a characteristic fashion. The interaction of erythropoietin with the dimeric erythropoietin receptor (EpoR), depicted in Figure 14-8, exemplifies the binding of a cytokine to its receptor. The structural homology among cytokines is evidence that they all evolved from a common ancestral protein. Likewise, the various receptors undoubtedly evolved from a single common ancestor.

Erythropoietin

Erythropoietin

Membrane surface

Membrane surface

▲ FIGURE 14-8 Structure of erythropoietin bound to the extracellular domains of a dimeric erythropoietin receptor (EpoR). Erythropoietin contains four conserved long a helices that are folded in a particular arrangement. The extracellular domain of an EpoR monomer is constructed of two subdomains, each of which contains seven conserved p strands folded in a characteristic fashion. Side chains of residues on two of the helices in erythropoietin contact loops on one EpoR monomer, while residues on the two other Epo helices bind to the same loop segments in a second receptor monomer, thereby stabilizing the dimeric receptor. The structures of other cytokines and their receptors are similar to erythropoietin and EpoR. [Adapted from R. S. Syed et al., 1998, Nature 395:511.]

Whether or not a cell responds to a particular cytokine depends simply on whether or not it expresses the corresponding (cognate) receptor. Although all cytokine receptors activate similar intracellular signaling pathways, the response of any particular cell to a cytokine signal depends on the cell's constellation of transcription factors, chromatin structures, and other proteins relating to the developmental history of the cell. If receptors for prolactin or thrombopoi-etin, for example, are expressed experimentally in an ery-throid progenitor cell, the cell will respond to these cytokines by dividing and differentiating into red blood cells, not into mammary cells or megakaryocytes.

Figure 14-9 summarizes the intracellular signaling pathways activated when the EpoR binds erythropoietin. Stimulation of other cytokine receptors by their specific ligands activates similar pathways. All these pathways eventually lead to activation of transcription factors, causing an increase or decrease in expression of particular target genes. Here we focus on the JAK-STAT pathway; the other pathways are discussed in later sections.

EpoR

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