Induction of DNA damage by UVB and UVA radiation may generate mutations and genomic instability leading to carcinogenesis. Therefore, skin cells being repeatedly exposed to ultraviolet (UV) light have acquired multilayered protective mechanisms to avoid malignant transformation. Besides extensive DNA repair mechanisms, the damaged skin cells can be eliminated by induction of apoptosis, which is mediated through the action of tumor suppressor p53. In order to prevent the excessive loss of skin cells and to maintain the skin barrier function, apoptotic pathways are counteracted by anti-apoptotic signaling including the AKT/mTOR pathway. However, AKT/mTOR not only prevents cell death, but is also active in cell cycle transition and hyper-proliferation, thereby also counteracting p53. In turn, AKT/mTOR is tuned down by the negative regulators being controlled by the p53. This inhibition of AKT/mTOR, in combination with transactivation of damage-regulated autophagy modulators, guides the p53-mediated elimination of damaged cellular components by autophagic clearance. Alternatively, p53 irreversibly blocks cell cycle progression to prevent AKT/mTOR-driven proliferation, thereby inducing premature senescence. Conclusively, AKT/mTOR via an extensive cross talk with p53 influences the UV response in the skin with no black and white scenario deciding over death or survival.

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Although nuclear factor-jB (NF-jB) usually exerts anti-apoptotic activity, upon activation by interleukin-1 (IL-1) it enhances ultraviolet-B radiation (UVB)-induced apoptosis. This paradoxical effect is associated with NF-jB-dependent pronounced secretion of tumour necrosis factor-a (TNF) which activates TNF-R1 in an autocrine fashion to enhance UVB-induced apoptosis. We demonstrate that sustained TNF transcription in UVB þ IL-1-treated cells involves complete abrogation of the negative feedback loop of NF-jB preventing IjBa resynthesis, hence allowing uncontrolled NF-jB activity. We show that IjBa is not transcriptionally inhibited but resynthesized protein is immediately marked for degradation due to persistent inhibitor of jB kinaseb (IKKb) activity. Continuous IKKb phosphorylation and activation is caused by UVB-mediated inhibition of the phosphatase PP2A. This study demonstrates that the cellular response to different NF-jB activators may be converted to the opposite reaction when both stimuli act in concert. Our data shed new light on the significance of negative feedback regulation of NF-jB and identifies PP2A as the key regulator of this process. The transcription factor nuclear factor-kB (NF-kB) is involved in many cellular responses. It comprises five proteins: p50/ p105, p52/p100, p65, c-Rel and RelB that exist as homo-and heterodimers, p65/p50 being the most abundant form. In unstimulated cells, NF-kB is sequestered in the cytoplasm through interaction with the inhibitory protein IkBa that masks its nuclear localization signal. 1 NF-kB (p65/p50) is mostly activated by pro-inflammatory mediators, including tumour necrosis factor-a (TNF), interleukin-1 (IL-1) or LPS. Activated receptors mediate activation of a multi subunit inhibitor of kB kinase (IKK) complex consisting of IKKa, -b and -g. Activated IKK acts through phosphorylation of IKKb at Ser177/181, subsequently catalysing phosphorylation of inhibitor of kBa (IkBa) at Ser32/36, leading to its polyubiquitination and proteasomal degradation. Released NF-kB translocates into the nucleus to activate responsive genes, among these the one encoding IkBa. 2 Nuclear export of resynthesized IkBa is more potent than import, allowing cytosolic localization of the inactive complex, thus creating a negative feedback loop. 3 As NF-kB serves many different functions, tight regulation by the negative feedback loop is crucial. Only highly controlled and transient expression of NF-kB-driven genes ensures proper function. Uncontrolled NF-kB activity is linked to transformation, proliferation, suppression of apoptosis and metastasis. 4,5 Thus, strategies interfering with signalling pathways activating NF-kB have become major targets for anticancer interventions. 6 We have previously shown that stimulus-dependent activation of NF-kB can result in completely opposite effects. Stimulation with IL-1 protects keratinocytes and epithelial cells from cytotoxic effects of death ligands in an NF-kB-dependent manner by upregulation of anti-apoptotic cFLIP and cIAPs. 7 In contr...

There is increasing evidence that hereditary factors play a greater role in ovarian cancer than in any of the other common cancers of adulthood. This is attributable, to a large extent, to a high frequency of mutations in the BRCA1 or BRCA2 genes. In Poland, 3 common founder mutations in BRCA1 account for the majority of families with identified BRCA mutations. Our study was conducted in order to estimate the prevalence of any of 3 founder BRCA1 mutations (5382insC, C61G and 4153delA) in 364 unselected women with ovarian cancer, and among 177 women with ovarian cancer and a family history of breast or ovarian cancer. A mutation was identified in 49 out of 364 unselected women with ovarian cancer (13.5%) and in 58 of 177 women with familial ovarian cancer (32.8%). The majority of women with ovarian cancer and a BRCA1 mutation have no family history of breast or ovarian cancer. The high frequency of BRCA1 mutations in Polish women with ovarian cancer supports the recommendation that all Polish women with ovarian cancer should be offered testing for genetic susceptibility, and that counseling services be made available to them and to their relatives. It is important that mutation surveys be conducted in other countries prior to the introduction of national genetic screening programs.

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