p38 mitogen-activated protein kinase (MAPK) mediates cellular responses to injurious stress and immune signaling. Among the multiple p38 isoforms, p38α is the most widely expressed in adult tissues and can be targeted by various pharmacological inhibitors. Here we investigated how p38α activation is linked to cell type-specific outputs using mouse models of cutaneous inflammation. We showed that both myeloid and epithelial p38α can signal to evoke inflammatory responses, yet the mode of skin irritation determines the cell type in which p38α serves the function. In addition, myeloid p38α induces self-limitation of acute inflammation via activation of MSK-dependent anti-inflammatory gene expression. These suggest a dual role of p38α in regulation of inflammation, and reveal a mixed potential for its inhibition as a therapeutic strategy.

Filamentous phage infection induces the synthesis of large amounts of an Escherichia coli protein, phage shock protein (Psp), the product of a previously undescribed gene. This induction is due to the phage gene IV protein, pIV, an integral membrane protein. The uninduced level of Psp is undetectable, but when induced by prolonged synthesis of pIV, it can become one of the most abundant proteins in the cell. Psp is also synthesized transiently in response to several stresses (heat, ethanol, and osmotic shock). High-level synthesis occurs only after extreme treatment. Unlike the members of the heat shock regulon, Psp induction does not require the heat shock sigma factor, sigma 32; some stimuli that elicit sigma 32-dependent heat shock proteins do not induce Psp synthesis. The level of Psp induction after extreme stress is even higher in sigma 32 mutant cells, which are unable to mount a normal heat shock response, suggesting that these parallel stress responses are interrelated.

Signaling pathways regulating the differentiation program of epidermal cells overlap widely with those activated during apoptosis. How differentiating cells remain protected from premature death, however, is still poorly defined. We show here that the phosphoinositide 3-kinase (PI3K)/Akt pathway is activated at early stages of mouse keratinocyte differentiation both in culture and in the intact epidermis in vivo. Expression of active Akt in keratinocytes promotes growth arrest and differentiation, whereas pharmacological blockade of PI3K inhibits the expression of "late" differentiation markers and leads to death of cells that would otherwise differentiate. Mechanistically, the activation of the PI3K/Akt pathway in keratinocyte differentiation depends on the activity of the epidermal growth factor receptor and Src families of tyrosine kinases and the engagement of E-cadherin-mediated adhesion. During this process, PI3K associates increasingly with cadherin-catenin protein complexes bearing tyrosine phosphorylated YXXM motifs. Thus, the PI3K signaling pathway regulates the choice between epidermal cell differentiation and death at the cross-talk between tyrosine kinases and cadherin-associated catenins.The epidermis is a self-renewing stratified epithelium in which the loss of terminally differentiated cells from its surface is balanced by cells that leave the proliferative basal layer and enter differentiation (1, 2). Because a metabolically dead cornified cell envelope is the end point of epidermal differentiation, this process may be viewed as a specialized form of programmed cell death (3). Moreover, the apoptotic program and keratinocyte differentiation share overlapping signaling effector mechanisms (4). Notably, the caspase-3 cysteine protease, an integral component of the cell death machinery, was implicated recently in embryonic keratinocyte differentiation control downstream of Notch1 (5), and activation of the related caspase-14 has been reported during adult keratinocyte differentiation (6). Nevertheless, "canonical" apoptosis and epidermal differentiation are distinct processes, with diverse execution times and biological outcomes; the former leads to the elimination of individual dead cells from tissues within hours, whereas the latter relies on the survival and synchronized maturation of whole sheets of cells over the course of weeks. Thus, an outstanding question is how keratinocytes can activate arrays of death-inducing signals during differentiation and yet remain protected from premature death.A candidate pathway for the survival of differentiating keratinocytes is the signaling module formed by the Class IA PI3K 4 and the downstream serine-threonine kinase Akt effectors (Akt/PKB-1, -2, and -3 isoforms) (7). The PI3K family is divided into three distinct classes (Class I, II, and III) based on primary structure, substrate specificity, and mode of regulation (8). Class I PI3Ks include four distinct p110 catalytic isoforms, further divided into Class IA (-␣, -␤, -␦) and IB (-␥); among these, p110...

Loss-of-function mutations in Whn (Hfh 11), a winged-helix/forkhead transcription factor, result in the nude mouse phenotype. To determine the whn expression pattern during development, we utilized mice in which a beta-galactosidase reporter gene was placed under the control of the wild-type whn promoter by homologous recombination (M. Nehls et al., 1996, Science 272, 886-889). Sites of reporter expression were confirmed by immunohistochemical staining for Whn protein or by in situ hybridization for whn mRNA. At all developmental stages, whn expression is restricted to epithelial cells. In addition to the skin and thymus, whn is expressed in the developing nails, nasal passages, tongue, palate, and teeth. In embryonic epidermis, suprabasal cells induce whn expression at the same time that terminal differentiation markers first appear. As the epidermis matures, whn promoter activity is found primarily in the first suprabasal layer, which contains keratinocytes in the early stages of terminal differentiation. In developing and mature anagen hair follicles, whn is expressed at high levels in the postmitotic precursor cells of the hair shaft and inner root sheath. Though principally associated with terminal differentiation, whn expression is also detected in progenitor cell compartments; in the hair bulb matrix and basal epidermal layer, a small subclass of cells expresses whn, while in the outer root sheath, whn promoter activity is induced as the follicle completes its elongation. Within these compartments, rare cells exhibit both whn expression and the nuclear proliferation marker Ki-67. The results suggest that whn expression encompasses the transition from a proliferative to a postmitotic state and that whn regulates the initiation of terminal differentiation.