Transforming growth factor: signal transduction pathways, cell cycle mediation, and effects on hematopoiesis

Transforming growth factor-beta (TGF-beta) is a potent growth inhibitor of various cell types including hematopoietic cells. Two receptors, TGF beta R I and TGF beta RII, govern the interaction between the cell and the TGF-bet a ligand. Primary binding of the ligand occurs with the RII receptor, promo ting formation of a heterodimer with RI and activation of signaling. This i nduces transient association of Smad proteins with the receptors. Smad 3 an d 4 may be involved in the TGF-beta -induced G(1) arrest. TGF-beta (1) down -regulates G(1) and G(2) cyclin-dependent kinases (cdks) and cyclins in ter ms of both kinase activity and protein amount. TGF-beta (1) also inhibits p hosphorylation of the product of the retinoblastoma tumor suppressor gene ( pRb) at multiple serine and threonine residues in human myeloid leukemia ce lls. The underphosphorylated pRb associates with transcription factor E2F-4 in G(1) phase, whereas the phosphorylated pRb mainly binds to E2F-1 and E2 F-3. Because TGF-beta (1) up-regulates p130(pRb family member)/E2F-4 comple x formation and down-regulates p107(pRb family member)/E2F-4 complex format ion, with E2F-4 levels remaining constant, these results suggest that E2F-4 is switched from p107 to pRb and p130 when cells exit from the cell cycle and arrest in G(1) by the action of TGF-beta (1). The "cdk inhibitor" p27 i s both a positive and a negative regulator of TGF-beta (1)-mediated cell cy cle control. Although TGF-beta (1) has been reported to be a selected inhib itor of normal primitive hematopoietic stem cells, TGF-beta inhibits both p rimitive and more differentiated myeloid leukemia cell lines.