Molecular Mechanisms of Ultraviolet Radiation Carcinogenesis

Ananthaswamy, Honnavara N.; Pierceall, William E.

doi:10.1111/j.1751-1097.1990.tb08452.x

Cited by 359 publications

(206 citation statements)

References 145 publications

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“…Activating mutations in the Ras oncogene or alterations in upstream or downstream signaling pathways are frequently present in premalignant and malignant human skin neoplasia such as actinic keratoses, SCCs, and BCCs, suggesting its importance in cutaneous carcinogenesis (13)(14)(15). To get insights into the regulation of CCL27 expression in keratinocyte-derived tumors, we analyzed the expression of CCL27 in HaCaT cell lines transfected with the activated H-RasV12 oncogene (Fig.…”

Section: Activation Of Ras Signaling Suppresses Ccl27 Expression In Kmentioning

confidence: 99%

Tumor immune escape by the loss of homeostatic chemokine expression

Pivarcsi

Müller

Hippe

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

123

101

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The novel keratinocyte-specific chemokine CCL27 plays a critical role in the organization of skin-associated immune responses by regulating T cell homing under homeostatic and inflammatory conditions. Here we demonstrate that human keratinocyte-derived skin tumors may evade T cell-mediated antitumor immune responses by down-regulating the expression of CCL27 through the activation of epidermal growth factor receptor (EGFR)-Ras-MAPKsignaling pathways. Compared with healthy skin, CCL27 mRNA and protein expression was progressively lost in transformed keratinocytes of actinic keratoses and basal and squamous cell carcinomas. In vivo, precancerous skin lesions as well as cutaneous carcinomas showed significantly elevated levels of phosphorylated ERK compared with normal skin, suggesting the activation of EGFR-Ras signaling pathways in keratinocyte-derived malignancies. In vitro, exogenous stimulation of the EGFR-Ras signaling pathway through EGF or transfection of the dominant-active form of the Ras oncogene (H-RasV12) suppressed whereas an EGFR tyrosine kinase inhibitor increased CCL27 mRNA and protein production in keratinocytes. In mice, neutralization of CCL27 led to decreased leukocyte recruitment to cutaneous tumor sites and significantly enhanced primary tumor growth. Collectively, our data identify a mechanism of skin tumors to evade host antitumor immune responses.cancer ͉ CCL27/CTACK ͉ skin ͉ immune surveillance ͉ EGDR/R pathway

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Section: Activation Of Ras Signaling Suppresses Ccl27 Expression In Kmentioning

confidence: 99%

Tumor immune escape by the loss of homeostatic chemokine expression

Pivarcsi

Müller

Hippe

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

123

101

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“…Exposure to solar ultraviolet (UV) radiation is unambiguously associated with skin cancer [1,2]. UVB (280-320 nm) is directly absorbed by DNA and induces damage such as cyclobutane pyrimidine dimers and (6-4) photoproducts [3,4], contributing to carcinogenicity.…”

Section: Introductionmentioning

confidence: 99%

Coexposure to benzo[a]pyrene and UVA induces phosphorylation of histone H2AX

Toyooka

Ibuki

2005

FEBS Letters

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Phosphorylation of histone H2AX (termed c-H2AX) was recently identified as an early event after induction of DNA double strand breaks (DSBs). We have previously shown that coexposure to benzo[a]pyrene (BaP), a wide-spread environmental carcinogen, and ultraviolet A (UVA), a major component of solar UV radiation, induced DSBs in mammalian cells. In the present study, we examined whether coexposure to BaP and UVA generates c-H2AX in CHO-K1 cells. Single treatment with BaP (10 À9-10 À7 M) or UVA ($2.4 J/cm 2 ) did not result in c-H2AX, however, coexposure drastically induced foci of c-H2AX in a dose-dependent manner. c-H2AX could be detected even at very low concentration of BaP (10 À9 M) plus UVA (0.6 J/cm 2 ), which did not change cell survival rates. NaN 3 effectively inhibited the formation of c-H2AX induced by coexposure, indicating the contribution of singlet oxygen. This is the first evidence that coexposure to BaP and UVA induced DSBs, involving c-H2AX.

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“…I rradiation of DNA with UV light produces a variety of photoproducts that block DNA replication (1)(2)(3)(4)(5)(6). When an SOS response is induced by UV irradiation, these photoproducts are bypassed with modest efficiency by DNA polymerase and give rise to mutations (5,6).…”

mentioning

confidence: 99%

The Dewar photoproduct of thymidylyl(3′→5′)- thymidine (Dewar product) exhibits mutagenic behavior in accordance with the “A rule”

Lee

Bae

Choi

2000

Proc. Natl. Acad. Sci. U.S.A.

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In contrast to the highly mutagenic pyrimidine(6 -4)pyrimidone photoproduct, its Dewar valence isomer (Dewar product) has low mutagenic potential and produces a broad range of mutations [LeClerc, J. E., Borden, A. & Lawrence, C. W. (1991) Proc. Natl. Acad. Sci. USA 88, 9685-9689]. To determine the origin of the mutagenic property of the Dewar product, we used experimental NMR restraints and molecular dynamics to determine the solution structure of a Dewar-lesion DNA decamer duplex. This DNA decamer duplex (DW͞GA duplex) contains a mismatched base pair between the 3 T residue of the Dewar lesion (T6) and an opposed G residue (G15). The 3 T (T6) of the Dewar lesion formed stable hydrogen bonds with the opposing G15 residue. However, the helical bending and unwinding angles of the DW͞GA duplex were much larger than those of a second duplex that contains the Dewar lesion and opposing A15 and A16 residues (DW͞AA duplex). The DW͞GA duplex showed poorer stacking interactions at the two bases of the Dewar product and at the adjacent A7⅐T14 base pair than did the DW͞AA duplex. These structural features imply that no thermal stability or conformational benefit is obtained by incorporating a G instead of an A opposite the 3 T of the Dewar lesion. These properties may thus facilitate the preferential incorporation of an A in accordance with the A rule during translesion replication and lead to the low frequency of 3 T3 C mutations observed at this site.I rradiation of DNA with UV light produces a variety of photoproducts that block DNA replication (1-6). When an SOS response is induced by UV irradiation, these photoproducts are bypassed with modest efficiency by DNA polymerase and give rise to mutations (5, 6). This process has been termed translesion replication (TR) or bypass synthesis, and mutations are caused by the tendency of DNA polymerase to insert an incorrect nucleotide opposite the lesion during TR (7,8).Although both the pyrimidine (6-4)pyrimidone photoproduct [(6-4) adduct], which is one of the major classes of UV-induced DNA photoproducts (9, 10), and its Dewar valence isomer (Dewar product) (Fig. 1A) cause mutations during TR, their mutagenic properties differ. The (6-4) adduct is highly mutagenic and yields a specific mutation (6,11,12). In SOS-induced Escherichia coli cells, the marked preference for the insertion of a guanine residue opposite the 3Ј T of (6-4) adducts during TR leads to a predominant 3Ј T3C transition with 85% replicating error frequency (6). In contrast, the Dewar product is less mutagenic and induces a broader range of mutations than does the (6-4) adduct (6, 12). In SOS-induced E. coli cells, adenine was found to be incorporated into the site opposite the 3Ј T of the Dewar product with a frequency of 72%, whereas G was incorporated only 21% of the time (6). Thus, the 3Ј T3C transition, which is the major class of mutations induced by the Dewar product, is produced with 13% replicating error frequency during TR (6).Enzyme repair rates of 49-residue oligonucleotides that contain site-spec...

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Molecular Mechanisms of Ultraviolet Radiation Carcinogenesis

Cited by 359 publications

References 145 publications

Tumor immune escape by the loss of homeostatic chemokine expression

Tumor immune escape by the loss of homeostatic chemokine expression

Coexposure to benzo[a]pyrene and UVA induces phosphorylation of histone H2AX

The Dewar photoproduct of thymidylyl(3′→5′)- thymidine (Dewar product) exhibits mutagenic behavior in accordance with the “A rule”

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