Catherine M. Woods

EGF-R as a hemopoietic growth factor receptor: The c-erbB product is present in chicken erythrocytic progenitors and controls their self-renewal

c-erbB, encoding the EGF receptor (EGF-R), was originally identified as the cellular homolog of a chicken leukemia oncogene. In humans, EGF-R is distributed widely except in hemopoietic tissues, and its amplification is associated with epidermal and glial malignancies. Here we show that c-erbB is present in normal chicken erythrocytic progenitors and transmits the mitogenic signal induced by TGF alpha. Cells that contain high affinity EGF-R are at approximately the BFU-E stage, and their long-term renewal can be induced by TGF alpha. Upon addition of insulin and erythropoietin, they can be induced to terminally differentiate into red cells. We previously demonstrated that v-erbA blocks differentiation of chicken erythrocytic progenitors but does not abrogate their growth factor dependence for proliferation. These data indicate that proliferation and differentiation are not necessarily coupled in these cells. They also demonstrate a direct role of c-erbB in the control of self-renewal of normal chicken erythrocytic progenitors and could account for the predominant leukemogenic potential of the chicken erbB gene.

Degradation of unassembled α- and β-spectrin by distinct intracellular pathways: Regulation of spectrin topogenesis by β-spectrin degradation

Abstract Analysis of the turnover of unassembled proteins during the assembly of the erythroid membrane skeleton has revealed that α- and β-spectrin, two structurally related, high molecular weight proteins, are degraded in a selective manner by two distinct intracellular pathways. Unassembled α-spectrin (t12 ⋍2 hr) is degraded by a system with all the pharmacological characteristics of a membrane-bound, lysosomal-type pathway. This result illustrates for the first time the selective degradation of an intracellular short-lived, unassembled protein by a lysosomal pathway. In contrast, unassembled β-spectrin is degraded extremely rapidly (t12 ⋍ 15–20 min at 38°C) by a soluble cytoplasmic system in an apparently ATP-independent manner. These observations suggest that the selective and rapid degradation of β-spectrin serves an important regulatory role in the topogenesis of the spectrinbased membrane skeleton in the chicken erythrocyte.

Modulation of experimental autoimmune encephalomyelitis by VLA-2 blockade

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS). Adhesion molecules play important roles in cell–cell and cell–extracellular matrix (ECM) interactions in inflammation. Blocking the interaction between inflammatory cells and vascular endothelia can prevent cell entry into tissues and harmful inflammatory responses, that is, autoimmunity, but could also limit immunosurveillance by anti‐viral T cells in sites of infection or latency. Development of progressive multifocal leukoencephalopathy in patients treated with antibody against very late antigen (VLA)‐4 prompted us to explore an alternative therapeutic approach. We used an antibody against the integrin α2, VLA‐2, that interacts with ECM, not vascular endothelium. SJL/J mice were sensitized with myelin proteolipid protein (PLP)139–151 peptide to induce experimental autoimmune encephalomyelitis (EAE), an animal model for MS. Treatment of mice with VLA‐2 antibody suppressed clinical signs and CNS inflammation of EAE, when antibody was given immediately after disease onset. In contrast, VLA‐4 or VLA‐2 antibody treatment of mice during the priming or remission phase of EAE had minor effects on the disease’s clinical course. No differences were found in lymphoproliferative responses to PLP139–151 among treatment groups. Data suggest that blocking cell–ECM interactions can be an alternative therapy for MS.