KLF6, a candidate tumor suppressor gene mutated in prostate cancer.

Kruppel-like factor 6 (KLF6) is a zinc finger transcription factor of unknown function. Here, we show that the KLF6 gene is mutated in a subset of human prostate cancer. Loss-of-heterozygosity analysis revealed that one KLF6 allele is deleted in 77% (17 of 22) of primary prostate tumors. Sequence analysis of the retained KLF6 allele revealed mutations in 71% of these tumors. Functional studies confirm that whereas wild-type KLF6 up-regulates p21 (WAF1/CIP1) in a p53-independent manner and significantly reduces cell proliferation, tumor-derived KLF6 mutants do not. Our data suggest that KLF6 is a tumor suppressor gene involved in human prostate cancer.

Red cell membrane disorders.

Significant advances have been made in our understanding of the structural basis for altered cell function in various inherited red cell membrane disorders with reduced red cell survival and resulting hemolytic anemia. The current review summarizes these advances as they relate to defining the molecular and structural basis for disorders involving altered membrane structural organization (hereditary spherocytosis [HS] and hereditary elliptocytosis [HE]) and altered membrane transport function (hereditary overhydrated stomatocytosis and hereditary xerocytosis). Mutations in genes encoding membrane proteins that account for these distinct red cell phenotypes have been identified. These molecular insights have led to improved understanding of the structural basis for altered membrane function in these disorders. Weakening of vertical linkage between the lipid bilayer and spectrin-based membrane skeleton leads to membrane loss in HS. In contrast, weakening of lateral linkages among different skeletal proteins leads to membrane fragmentation and decreased surface area in HE. The degrees of membrane loss and resultant increases in cell sphericity determine the severity of anemia in these two disorders. Splenectomy leads to amelioration of anemia by increasing the circulatory red cell life span of spherocytic red cells that are normally sequestered by the spleen. Disordered membrane cation permeability and resultant increase or decrease in red cell volume account for altered cellular deformability of hereditary overhydrated stomatocytosis and hereditary xerocytosis, respectively. Importantly, splenectomy is not beneficial in these two membrane transport disorders and in fact contraindicated due to severe postsplenectomy thrombotic complications.

Transplantation of murine bone marrow without prior host irradiation.

The experiments presented test the hypothesis that pluripotential stem cells (assayed in the mouse as CFU-S) are normally not in cycle and that the failure of normal marrow transfusions to take in normal recipients is due to the absence of a stimulus to turn CFU-S into cycle. Following marrow transfusion from male donors into female isogeneic recipients, spleen, liver, and various parts of the skeleton were shielded to protect transfused donor cells from lethal doses of radiation gives to the rest of the body. Percentages of hemopoietic donor and host cells were subsequently determined by karyotyping C banded marrow and spleen metaphases and identifying of Y chromosome. The results support the notion that the failure of normal marrow to take in normal recipients is not due to inadequate numbers of transfused cells. Permanent colonization by donor cells, however, requires not only triggering CFU-S into cycle, but also emptying of 'niches' normally occupied by endogenous CFU-S. Partial body radiation meets both requirements. In addition, the results indicate that recently arrived donor cells, protected in the shielded portion of the body, seed more readily into the irradiated areas of the skeleton than do similarly protected host cells.