In cells of higher eukaryotes, cyclin D-dependent kinases Cdk4 and Cdk6 and, possibly, cyclin E-dependentCdk2 positively regulate the G 1-to S-phase transition, by phosphorylating the retinoblastoma protein (pRb), thereby releasing E2F transcription factors that control S-phase genes. Here we performed microinjection and transfection experiments using rat R12 fibroblasts, their derivatives conditionally overexpressing cyclins D1 or E, and human U-2-OS cells, to explore the action of G~ cyclins and the relationship of E2F and cyclin E in S-phase induction. We demonstrate that ectopic expression of cyclin E, but not cyclin D1, can override G~ arrest imposed by either the p16 INK4a Cdk inhibitor specific for Cdk4 and Cdk6 or a novel phosphorylation-deficient mutant pRb. Several complementary approaches to assess E2F activation, including quantitative reporter assays in live cells, showed that the cyclin E-induced S phase and completion of the cell division cycle can occur in the absence of E2F-mediated transactivation. Together with the ability of cyclin E to overcome a G~ block induced by expression of dominant-negative mutant DP-1, a heterodimeric partner of E2Fs, these results provide evidence for a cyclin E-controlled S phase-promoting event in somatic cells downstream of or parallel to phosphorylation of pRb and independent of E2F activation. They furthermore indicate that a lack of E2F-mediated transactivation can be compensated by hyperactivation of this cyclin E-controlled event.[Key Words: Cyclin E; cyclin D1; p16; pRb phosphorylation; E2F; S phase] Received November 11, 1996; revised version accepted April 9, 1997.Progression from G~ to S phase of the mammalian cell cycle is regulated by cyclin D-dependent kinases Cdk4 and Cdk6 complexed to D-type cyclins, and by Cdk2 bound to cyclins E or A

PDT can be an effective noninvasive method to treat actinic cheilitis of the lower lip.

Hematopoiesis occurs in the liver and the bone marrow (BM) during murine development. Newborn mice with a ubiquitous deletion of I kappa B alpha develop a severe hematological disorder characterized by an increase of granulocyte/erythroid/monocyte/macrophage colony-forming units (CFU-GEMM) and hypergranulopoiesis. Here, we report that this particular myeloproliferative disturbance is mediated by continuously deregulated perinatal expression of Jagged1 in I kappa B alpha-deficient hepatocytes. The result is a permanent activation of Notch1 in neutrophils. In contrast, in mice with a conditional deletion of I kappa B alpha only in the myeloid lineage (ikba(flox/flox) x LysM-Cre) and in fetal liver cell chimeras (ikba(FL delta/FL delta)), a cell-autonomous induction of the myeloproliferative disease was not observed. Coculture of I kappa B alpha-deficient hepatocytes with wild-type (wt) BM cells induced a Jagged1-dependent increase in CFUs. In summary, we show that cell-fate decisions leading to a premalignant hematopoietic disorder can be initiated by nonhematopoietic cells with inactive I kappa B alpha.

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DNA damage caused by ultraviolet (UV) irradiation is considered the main etiologic factor contributing to the development of skin cancer. Systemic or topical application of antioxidants has been suggested as a protective measure against UV-induced skin damage. We investigated the effect of long-term oral administration of a combination of the antioxidants ascorbic acid (vitamin C) and D-alpha-tocopherol (vitamin E) in human volunteers on UVB-induced epidermal damage. The intake of vitamins C and E for a period of 3 mo significantly reduced the sunburn reaction to UVB irradiation. Detection of thymine dimers in the skin using a specific antibody revealed a significant increase of this type of DNA damage following UVB exposure. After 3 mo of antioxidant administration, significantly less thymine dimers were induced by the UVB challenge, suggesting that antioxidant treatment protected against DNA damage.

Our results corroborate the assumption that skin barrier dysfunction plays an essential role in the pathogenesis of CHE.

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