potential mechanisms involved in resistant phenotype of MCF-7breast carcinoma cells to ionizing radiation induced apoptosis

In the present study, we investigated the mechanisms of apoptosis resistance and the roles of the phosphorylation of BRCA1, p21, the Bax/Bcl-2 protein ratio and cell cycle arrest in IR-induced apoptosis in MCF-7 cells. X-irradiation, in particular at low dose (1 Gy), but not carbon ion irradiation, had a significant antiproliferative effect on the growth of MCF-7 cells. 1 Gy X-irradiation resulted in G1 and G2 phase arrest, but 4 Gy induced a significant G1 block. In contrast, carbon ion irradiation resulted in a significant accumulation in the G2 phase. Concomitant with the phosphorylation of H2AX induced by DNA damage,carbon ion irradiation resulted in an approximately 1.9–2.8-fold increase in the phosphorylation of BRCA1 on serine residue 1524, significantly greater than that detected for X-irradiation. Carbon ion irradiation caused a dramatic increase in p21 expression and drastic decrease in Bax expression compared with X-irradiation. The data implicated that phosphorylation of BRCA1 on serine residue 1524 might,at least partially, induce p21 expression but repress Bax expression. Together, our results suggested that the phosphorylation of BRCA1 at Ser-1524 might contribute to the G2 phase arrest and might be an upstream signal involved in preventing apoptosis signal via upregulation of p21 and downregulation of the Bax/Bcl-2 ratio.

Survivin表达在高LET射线诱导细胞凋亡中作用机理的初步研究；A Preliminary Study on Action Mechanisms of Survivin Expression in Cell Apoptosis Induced by High-LET Radiation

先前的研究表明,肿瘤细胞中survivin的高表达与细胞对高传能线密度(LET)射线的辐射抗性相关。研究了survivin表达在高LET射线诱导的细胞凋亡中的作用,发现抑制survivin表达对高LETC离子辐射诱导的Bcl-2和Bax表达没有明显的影响。在高LET射线辐照中,survivin可能通过抑制caspase-3和-9活性的途径,抑制了细胞凋亡。

Midlatitude Forcing Mechanisms for Glacier Mass Balance Investigated Using General Circulation Models

A process-oriented modeling approach is applied in order to simulate glacier mass balance for individual glaciers using statistically downscaled general circulation models (GCMs). Glacier-specific seasonal sensitivity characteristics based on a mass balance model of intermediate complexity are used to simulate mass balances of Nigardsbreen (Norway) and Rhonegletscher (Switzerland). Simulations using reanalyses (ECMWF) for the period 1979–93 are in good agreement with in situ mass balance measurements for Nigardsbreen. The method is applied to multicentury integrations of coupled (ECHAM4/OPYC) and mixed-layer (ECHAM4/MLO) GCMs excluding external forcing. A high correlation between decadal variations in the North Atlantic oscillation (NAO) and mass balance of the glaciers is found. The dominant factor for this relationship is the strong impact of winter precipitation associated with the NAO. A high NAO phase means enhanced (reduced) winter precipitation for Nigardsbreen (Rhonegletscher), typically leading to a higher (lower) than normal annual mass balance. This mechanism, entirely due to internal variations in the climate system, can explain observed strong positive mass balances for Nigardsbreen and other maritime Norwegian glaciers within the period 1980–95. It can also partly be responsible for recent strong negative mass balances of Alpine glaciers.

ACCRETION MECHANISMS ONTO PRIMORDIAL BLACK HOLES

We study the evolution of a primordial black hole (PBH) taking into account the presence of dark energy modeled by a general perfect fluid. In the specific case of a stationary non-self-gravitating test fluid, the competition between radiation accretion, Hawking evaporation and the accretion of such a fluid has been studied in detail. The evaporation of PBHs is quite modified at late times by these effects. We address further generalizations of this scenario to consider other types of fluids, and point out early developments of a nonstationary accretion model.

Investigation of mechanisms involved in ultraviolet B radiation-induced, T cell -mediated immune suppression

Cutaneous exposure to ultraviolet-B radiation (UVR) results in the suppression of cell-mediated immune responses such as contact hypersensitivity (CHS) and delayed-type hypersensitivity (DTH). This modulation of immune responses is mediated by local or systemic mechanisms, both of which are associated with the generation of antigen-specific suppressor T lymphocytes (Ts). UV-induced Ts have been shown to be CD3+CD4+CD8 − T cells that control multiple immunological pathways. However, the precise mechanisms involved in the generation and function of these immunoregulatory cells remain unclear. We investigated the cellular basis for the generation of UV-induced Ts lymphocytes in both local and systemic models of immune suppression, and further examined the pleiotrophic function of these immunoregulatory cells. ^ We used Thy1.1 and Thy1.2 congenic mice in a draining lymph node (DLN) cell transfer model to analyze the role played by epidermal Langerhans cells in the generation of Ts cells. We demonstrate that T cells tightly adhered to antigen-presenting cells (APC) from UV-irradiated skin are the direct progenitors of UV-induced Ts lymphocytes. Our studies also reveal that UV-induced DNA-damage in the form of cyclobutyl pyrimidine dimers (CPD) in the epidermal APC is crucial for the altered maturation of these adherent T cells into Ts. ^ We used TCR transgenic mice in an adoptive transfer model and physically tracked the antigen-specific clones during immune responses in unirradiated versus UV-irradiated mice. We demonstrate that UV-induced Ts and effector TDTH cells share the same epitope specificity, indicating that both cell populations arise from the same clonal progenitors. UVR also causes profound changes in the localization and proliferation of antigen-specific T cells during an immune response. Antigen-specific T cells are not detectable in the DLNs of UV-irradiated mice after 3 days post-immunization, but are found in abundance in the spleen. In contrast, these clones continue to be found in the DLNs and spleens of normal animals several days post-immunization. Our studies also reveal that a Th2 cytokine environment is essential for the generation of Ts in UV-irradiated mice. ^ The third part of our study examined the pleiotrophic nature of UV-induced Ts. We used a model for the induction of both cellular and humoral responses to human gamma-globulin (HGG) to demonstrate that UV-induced Ts lymphocytes can suppress DTH as well as antibody responses. (Abstract shortened by UMI.) ^

Ionizing radiation and short wavelength UV activate NF-κB through two distinct mechanisms

We examined the mechanisms by which two different types of photonic radiation, short wavelength UV (UV-C) and γ radiation, activate transcription factor NF-κB. Exposure of mammalian cells to either form of radiation resulted in induction with similar kinetics of NF-κB DNA binding activity, nuclear translocation of its p65(RelA) subunit, and degradation of the major NF-κB inhibitor IκBα. In both cases, induction of NF-κB activity was attenuated by proteasome inhibitors and a mutation in ubiquitin-activating enzyme, suggesting that both UV-C and γ radiation induce degradation of IκBs by means of the ubiquitin/proteasome pathway. However, although the induction of IκBα degradation by γ rays was dependent on its phosphorylation at Ser-32 and Ser-36, UV-C-induced IκBα degradation was not dependent on phosphorylation of these residues. Even the “super repressor” IκBα mutant, which contains alanines at positions 32 and 36, was still susceptible to UV-C-induced degradation. Correspondingly, we found that γ radiation led to activation of IKK, the protein kinase that phosphorylates IκBα at Ser-32 and Ser-36, whereas UV-C radiation did not. Furthermore, expression of a catalytically inactive IKKβ mutant prevented NF-κB activation by γ radiation, but not by UV-C. These results indicate that γ radiation and UV-C activate NF-κB through two distinct mechanisms.