Transforming Growth Factor: Signal Transduction Pathways,Cell Cycle Mediation,and Effects on Hematopoiesis

Transforming growth factor-β (TGF-β) is a potent growth inhibitor of various cell types including hematopoietic cells. Two receptors, TGFβRI and TGFβRII, govern the interaction between the cell and the TGF-β ligand. Primary binding of the ligand occurs with the RII receptor, promoting formation of a heterodimer with RI and activation of signaling. This induces transient association of Smad proteins with the receptors. Smad 3 and 4 may be involved in the TGF-β-induced G₁ arrest. TGF-β₁ down-regulates G₁ and G₂ cyclin-dependent kinases(cdks) and cyclins in terms of both kinase activity and protein amount. TGF- β ₁ also inhibits phosphorylation of the product of the retinoblastoma tumor suppressor gene (pRb) at multiple serine and threonine residues in human myeloid leukemia cells. The underphosphorylated pRb associates with transcription factor E2F-4 in G₁ phase, whereas the phosphorylated pRb mainly binds to E2F-1 and E2F-3. Because TGF-β₁ up-regulates p130(pRb family member)/E2F-4 complex formation and down-regulates p107(pRb family member)/E2F-4 complex formation, 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 G₁ by the action of TGF-β₁. The "cdk inhibitor" p27 is both a positive and a negative regulator of TGF-β₁-mediated cell cycle control. Although TGF-β₁ has been reported to be a selected inhibitor of normal primitive hematopoietic stem cells, TGF-β inhibits both primitive and more differentiated myeloid leukemia cell lines.