Regulation Of ckit And Scf

The promoters of the mouse and human c-kit genes lack any TATA boxes or CCAAT sequences, but there are numerous sites for binding of transcription factors, including Sp-1, AP-2, Ets, Myb, SCL (tal-1), GATA-1, and MITF (4,6,8). The promoter of the SCF gene has not been extensively characterized, but multiple transcription factor binding sites (including a TATA box and sites for Sp-1 and AP-2) have been identified for both mouse (185) and human (186).

The alternate splicing of exon 6 to generate SCF248 vs SCF220 presents possibilities for functional regulation. In normal mice, the ratio of expression of mRNAs for SCF248 and SCF220 differs between tissues (the ratio is approx 3:1 in bone marrow), and the ratio seems to be subject to modulation within a given cell type (4-7).

Soluble c-kit, i.e., the extracellular portion, is found at very high concentration in normal human serum—approx 325 ng/mL, which represents a molar excess of approx 30-fold over the concentration of soluble SCF in serum (3 ng/mL, itself relatively high compared with that for most cytokines) (4,5,7,14). Soluble c-kit can bind and thereby potentially sequester soluble or membrane-associated SCF and has been shown to block SCF action when supplied exogenously in vitro (5,7,187). Whether or not it has a physiologically important role of this type is not known. Several cell types (hematopoi-etic cells, mast cells, endothelial cells) release soluble c-kit in vitro (5-8), potentially subject to stimulation through PKC (6,8). The cleavage site is within the fifth Ig domain (31), probably very close to the transmembrane portion. In vivo, amounts of soluble c-kit appear to be increased in clinical disorders in which the prevalence of c-

kit-expressing cells is a feature, e.g., acute myeloid leukemia (AML) (8) and mastocytosis (188,189).

c-Kit is downregulated with maturation in most hematopoietic lineages, including the erythroid. Proteolytic release of soluble c-kit may represent one means of downregulat-ing amounts of c-kit at the cell surface. Another means is internalization upon SCF binding. SCF c-kit complexes can be internalized rapidly (<30 min) by association with clathrin (190), capping, and endocytosis of the coated pits (5). Internalization requires that c-kit be activated with respect to its kinase activity; in DA-1 cells (murine lymphoma cell line) transfected with c-kit, SCF-induced association of c-kit with clathrin was dependent on PI3K (190), and in MO7e cells, the steps after clathrin association were dependent on a Src family kinase(s) (191). The internalized c-kit is degraded in lysosomes or ubiquitinated and targeted for degradation by proteasomes (5,6).

At the level of gene transcription, various other cytokines can lead to downmodula-tion of c-kit, including transforming growth factor-P (TGF-P) and TNF-a, both of which tend to be inhibitory toward hematopoiesis (6,8). In the erythroid lineage, it is possible that SCL (tal-1) drives c-kit transcription at early stages (192) but inhibits it later as part of a pentameric complex that also contains Rb (along with E2A, Lmo-2, and Ldb1) (193). Under some circumstances, Sp-1 or GATA-1 may also be components of the transcription factor complexes regulating c-kit expression (194).

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