Bone morphogenetic protein (BMP) signaling induces hepatic expression of the peptide hormone hepcidin. Hepcidin reduces serum iron levels by promoting degradation of the iron exporter ferroportin. A relative deficiency of hepcidin underlies the pathophysiology of many of the genetically distinct iron overload disorders, collectively termed hereditary hemochromatosis. Conversely, chronic inflammatory conditions and neoplastic diseases can induce high hepcidin levels, leading to impaired mobilization of iron stores and the anemia of chronic disease. Two BMP type I receptors, Alk2 (Acvr1) and Alk3 (Bmpr1a), are expressed in murine hepatocytes. We report that liver-specific deletion of either Alk2 or Alk3 causes iron overload in mice. The iron overload phenotype was more marked in Alk3-than in Alk2-deficient mice, and Alk3 deficiency was associated with a nearly complete ablation of basal BMP signaling and hepci- IntroductionThe hepatic hormone hepcidin regulates serum iron levels in mice and humans by inducing degradation of the iron exporter, ferroportin. 1,2 Low ferroportin levels reduce intestinal iron absorption and the release of iron from macrophage stores. Human hereditary hemochromatosis is characterized by low hepcidin levels, leading to iron accumulation in liver, heart, and endocrine organs. 1,3 Similarly, hepcidin deficiency causes hepatic iron overload in mice. 2,4 In contrast, high hepcidin levels contribute to the anemia of chronic disease (ACD) by reducing iron bioavailability for erythropoiesis. 5,6 Recent studies have demonstrated a critical role for bone morphogenetic protein (BMP) signaling in the regulation of hepcidin expression by iron. [7][8][9][10][11] Binding of BMP ligands to type I and type II BMP receptors induces the type II receptor to phosphorylate and activate the type I receptor. The activated type I receptor, in turn, phosphorylates intracellular signaling molecules, including SMADs 1, 5, and 8. Phosphorylated SMADs 1, 5, and 8 bind SMAD4 and together translocate to the nucleus, where they activate the expression of genes, including hepcidin and the Id family of transcription factors. 12 Deficiency of Smad4, 10 the BMP coreceptor hemojuvelin, 13,14 or BMP6 15,16 in hepatocytes reduces expression of hepcidin 17,18 and induces iron overload. In addition, BMP signaling appears to have an important role in the induction of hepcidin expression by inflammatory mediators that are involved in ACD. 11,19,20 There are 4 type I BMP receptors: Alk1, Alk2, Alk3, and Alk6. The identity of the type I BMP receptor(s) responsible for iron-dependent signaling and the regulation of hepcidin expression in hepatocytes are unknown. Alk1 is predominantly expressed in the endothelium. Alk6 is expressed at low levels in murine liver, 21 and global Alk6 deficiency does not induce iron overload in mice (D. R. Campagna, P. J. Schmidt, and M.D.F., unpublished observations, January 2011). In contrast, Alk2 and Alk3 are abundantly expressed in hepatocytes. 21 To identify the type I BMP receptor required for th...

Key Points Presence of the BMP type I receptor Alk3 is required for interleukin-6 to induce hepatic hepcidin gene expression. Alk3 contributes to the induction of hypoferremia by interleukin-6.

The cell cycle is driven by the kinase activity of cyclin⅐cyclin-dependent kinase (CDK) complexes, which is negatively regulated by CDK inhibitor proteins. Recently, we identified INCA1 as an interaction partner and a substrate of cyclin A1 in complex with CDK2. On a functional level, we identified a novel cyclin-binding site in the INCA1 protein. INCA1 inhibited CDK2 activity and cell proliferation. The inhibitory effects depended on the cyclin-interacting domain. Mitogenic and oncogenic signals suppressed INCA1 expression, whereas it was induced by cell cycle arrest. We established a deletional mouse model that showed increased CDK2 activity in spleen with altered spleen architecture in Inca1 ؊/؊ mice. Inca1 ؊/؊ embryonic fibroblasts showed an increase in the fraction of S-phase cells. Furthermore, blasts from acute lymphoid leukemia and acute myeloid leukemia patients expressed significantly reduced INCA1 levels highlighting its relevance for growth control in vivo. Taken together, this study identifies a novel CDK inhibitor with reduced expression in acute myeloid and lymphoid leukemia. The molecular events that control the cell cycle occur in a sequential process to ensure a tight regulation, which is important for the survival of a cell and includes the detection and repair of genetic damage and the prevention of uncontrolled cell division.