Role of the p38 and MEK-½/p42/44 MAP Kinase Pathways in the Differential Activation of Human Immunodeficiency Virus Gene Expression by Ultraviolet and Ionizing Radiation

Abstract

Ultraviolet (UV) radiation is a potent activator of human immunodeficiency virus (HIV) gene expression in a HeLa cell clone having stably integrated copies of an HIVcat (cat gene under control of the HIV promoter) reporter construct, whereas ionizing radiation is ineffective. UV‐activated HIV gene expression is completely blocked by the specific p38 mitogen‐activated protein (MAP) kinase inhibitor SB203580 and by expression of a kinase‐inactive p38 mutant that interferes with normal p38 function, suggesting that this stress‐activated protein kinase plays an important role in UV‐mediated transcriptional activation of HIV. In support of these findings, we show here that Western blot analysis demonstrated rapid and significant activation of p38 MAP kinase by UV. On the other hand, γ‐radiation activated p38 MAP kinase very poorly in HeLa cells at both low and high doses at times (5–30 min) when UV radiation was effective. UV radiation also activated HIV gene expression (≤9‐fold) in 1G5 Jurkat T‐cells stably transfected with a luciferase reporter gene under control of the HIV promoter. In these cells, γ‐radiation stimulated HIV gene expression but to a lesser extent (≤3‐fold) and with different kinetics than after UV radiation, and this response was obliterated by the incubation of cells with the mitogen‐activated protein kinase/Erk kinase (MEK)‐½ inhibitor PD98059. This result suggests that in these cells signaling in response to γ‐radiation is transduced through the MEK‐½/p42/44 MAP kinase pathway to increase HIV gene expression. All combined, these results suggest that activation of p38 MAP kinase is necessary for efficient HIV gene expression triggered by DNA damaging agents, and, in a cell type‐specific manner, activation of the MEK‐½/p42/44 MAP kinase pathway is important for triggering a response to γ‐radiation. Thus, it appears as if UV signaling leading to HIV gene expression requires the p38 MAP kinase pathway whereas activation by γ‐radiation requires the MEK‐½/p42/44 MAP kinase pathway.

Mitogen-Activated Protein Kinases and Their Role in Radiation Response

“…96,97 A range of proinflammatory cytokines and environmental stresses can trigger the p38 MAPK cascade. The ability of ionizing radiation to regulate p38 MAPK activity appears to be highly variable, with different groups reporting either no activation, 98 weak activation, 99 or strong activation. 100,101 This is in contrast to the classic ERK and JNK pathways in which radiation-induced activation has been observed by many groups, in diverse cell types, and in response to low and high radiation doses.…”

p38 Mitogen-Activated Protein Kinase- and HuR-Dependent Stabilization of p21Cip1 mRNA Mediates the G1/S Checkpoint

“…Nevertheless, the ability of ionizing radiation to activate p38 MAPK has been controversial (29,38,44,49). Of note, recent evidence has suggested that the role of p38 MAPK in the responses to DNA damage may be especially important in p53-defective cells (39).…”

Photoprotective Effects of Carrageenans Against Ultravioletb-Induced Extracellular Matrix (Ecm) Damage in Keratinocytes

“…Ultraviolet radiation activates all three MAPKs (p38, JNK, ERK) in skin cells (Dent et al,2003). The activity of p38 due to ionising radiation is variable, showing either no activation (Kim et al,2002), weak activation (Taher et al,2000) or strong activation (Narang et al,2009), whereas activation of ERK (MEK1/2) and SAPK/JNK pathways has been observed in varied cell types, whether to low or high radiation (Munshi & Ramesh, 2013). UVB raised p38 and ERK phosphorylation between two and ten hours after exposure.…”