Polyamines regulate calcium fluxes in a rapid plasma membrane response

Activation of cell-surface receptors often evokes changes in Ca2+ fluxes leading to an increase in cytosolic Ca2+, a generally accepted mediator of many cell responses. The molecular mechanisms by which surface agonists elicit these changes in Ca2+ flux have remained elusive. An increase in the polyamines putrescine, spermidine and spermine, and their rate-regulating, synthetic enzyme ornithine decarboxylase (ODC), is one of the earliest events that occur during cell growth, replication and differentiation. However, the precise physiological roles of the polyamines remain enigmatic. Recently, we found that testosterone induces an early (less than 60s), Ca2+- and receptor-dependent stimulation of endocytosis, hexose transport and amino acid transport in mouse kidney cortex involving the proximal tubules. This response is associated with increased Ca2+ fluxes and a mobilization of intracellular calcium, and is thought to represent a direct, receptor-mediated action of testosterone on the surface membrane. Polyamine synthesis was previously found to be essential for the long-term effects of testosterone on mouse kidney. We now report that testosterone evokes a rapid (less than 30 s), transient increase in ODC activity and a sustained increase in polyamines in kidney cortex. This polyamine synthesis is obligatory for stimulation of membrane transport functions and Ca2+ fluxes. These findings form the basis for a new theory of information flow in stimulus-response coupling in which the polyamines serve as messengers to generate a Ca2+ signal by increasing Ca2+ influx and mobilizing intracellular calcium via a cation-exchange reaction.     

Chromosomally unstable mouse tumours have genomic alterations similar to diverse human cancers

Highly rearranged and mutated cancer genomes present major challenges in the identification of pathogenetic events driving the neoplastic transformation process. Here we engineered lymphoma-prone mice with chromosomal instability to assess the usefulness of mouse models in cancer gene discovery and the extent of cross-species overlap in cancer-associated copy number aberrations. Along with targeted re-sequencing, our comparative oncogenomic studies identified FBXW7 and PTEN to be commonly deleted both in murine lymphomas and in human T-cell acute lymphoblastic leukaemia/lymphoma (T-ALL). The murine cancers acquire widespread recurrent amplifications and deletions targeting loci syntenic to those not only in human T-ALL but also in diverse human haematopoietic, mesenchymal and epithelial tumours. These results indicate that murine and human tumours experience common biological processes driven by orthologous genetic events in their malignant evolution. The highly concordant nature of genomic events encourages the use of genomically unstable murine cancer models in the discovery of biological driver events in the human oncogenome.     

Effect of abnormal amino acid concentrations on blood-brain barrier

Zusammenfassung Nachweis, dass die i.p. Injektion grosser Mengen vonl-Tyrosin die Permeabilität der hypothetischen «Blut-Hirn-Schranke» beträchtlich herabsetzt. Pyridoxalphosphat verhindert nicht nur diese Hemmung, sondern steigert die Absorption vonl-Lysin.

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This work was supported by a grant to S.B.N. from the office of Navel Research No. N 00014-70-C-0151.