1: J Virol. 2004 Apr;78(7):3489-501. Transcriptional response of a common permissive cell type to infection by two diverse alphaherpesviruses. Ray N, Enquist LW. Department of Molecular Biology, Princeton University, Princeton, New Jersey 08544-1014, USA. Pseudorabies virus (PRV) and herpes simplex virus type 1 (HSV-1) are distantly related alphaherpesviruses whose natural hosts are pigs and humans, respectively. Adult infections of natural hosts are mild and rarely lethal. However, both viruses are also able to infect other hosts, often with lethal effects. In this report, we use the paradigm of infection of a common permissive cell type and microarray analysis to determine if these two diverse alphaherpesviruses engage similar or different cellular pathways to obtain a common outcome: productive infection. We compared cellular gene expression in growth-arrested, primary rat embryonic fibroblasts that were mock infected or infected with either purified PRV-Becker or HSV-1(F). Infections by either virus affect the transcription of more than 1,500 cellular genes by threefold or more. Few differences are detected early, and the majority of changes occur during the late stages of infection. Remarkably, the transcripts of about 500 genes are regulated in common, while the rest are regulated in a virus-specific manner. Genes whose expression is affected by infection fall into a diverse group of functional classes and cellular pathways. Furthermore, a comparison of the cellular response to HSV-1 infection of primary human and rat fibroblasts revealed unexpected diversity in the transcript profiles. PMID: 15016872 [PubMed - indexed for MEDLINE] --------------------------------------------------------------- 2: Proc Natl Acad Sci U S A. 2000 Dec 5;97(25):13824-9. Two distinct signaling pathways in hair cycle induction: Stat3-dependent and -independent pathways. Sano S, Kira M, Takagi S, Yoshikawa K, Takeda J, Itami S. Departments of Dermatology and Social and Environmental Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan. The hair follicle is an epidermal derivative that undergoes cycles of growth, involution, and rest. The hair cycle has well-orchestrated kinetics regulated by interactions between mesenchymal and epithelial cells, although the intracellular signals remain unclear. We previously established keratinocyte-specific Stat3-disrupted mice, by which we demonstrated that signal transducer and activator of transcription 3 (Stat3) is required for wound healing and anagen progression in the hair cycle. Growth factor-dependent migration of Stat3-disrupted keratinocytes was severely impaired, suggesting that not only wound healing but also telogen-to-anagen progression required organized keratinocyte migration in response to mesenchymal stimuli. In the present study, to examine whether Stat3 activation in keratinocytes is a prerequisite for hair cycle progression, we applied methods for experimental anagen induction to Stat3-disrupted mice. It was demonstrated that anagen was successfully induced in Stat3-disrupted as well as wild-type mice by chemical or mechanical stimulation, i.e. , by topical application of phorbol 12-myristate 13-acetate (PMA) or by hair plucking, respectively. This result indicated that anagen in these methods occurred in the absence of Stat3. Furthermore, PMA stimulated the migration of Stat3-disrupted keratinocytes in vitro, supporting a hypothesis that the protein kinase C (PKC) and Stat3 pathways occur independently in the postnatal anagen induction. Both Stat3-dependent and -independent migration of keratinocytes was inhibited by a phosphoinositide 3-kinase (PI3K) inhibitor, wortmannin. Therefore, we infer that entry into anagen is mediated by at least two distinct signaling pathways: Stat3-dependent pathway for spontaneous hair cycling and Stat3-independent (probably PKC-dependent) pathway for exogenously induced hair cycling, whereas both pathways require PI3K activation. PMID: 11087819 [PubMed - indexed for MEDLINE] --------------------------------------------------------------- 3: Genes Cells. 1999 Jun;4(6):363-73. Critical role of the membrane-proximal, proline-rich motif of the interleukin-2 receptor gammac chain in the Jak3-independent signal transduction. Tsujino S, Miyazaki T, Kawahara A, Maeda M, Taniguchi T, Fujii H. Department of Immunology, Graduate School of Medicine and Faculty of Medicine, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan. BACKGROUND: The interleukin-2 receptor (IL-2R) consists of three subunits, the IL-2Ralpha, IL-2Rbetac, and IL-2Rgammac chains. The essential role of the IL-2Rgammac cytoplasmic domain, consisting of 86 amino acids, in signal transmission has been well documented. Particularly, the carboxyl ter-minal region containing 48 amino acids. is essential for the association with and activation of the Jak3 protein tyrosine kinase. On the other hand, little is known about the role of the rest of the IL-2Rgammac cytoplasmic region consisting of the membrane-proximal 38 amino acids. RESULTS: We show that a truncated mutant form of IL-2Rgammac which lacks the membrane-distal 48 amino acids is still capable of inducing the activation of Jak1 and Stat3/Stat5 in the absence of Jak3 activation. This membrane-proximal region can also mediate the IL-2-induced tyrosine phosphorylation of the p85 subunit of phosphatidylinositol-3-kinase (PI3K). Furthermore, these signalling events are completely abrogated when mutations are introduced into the proline-rich motif in this region. CONCLUSIONS: In this study, we identified a Jak3-independent signalling pathway(s) from the membrane-proximal region of IL-2Rgammac. Our results indicate that the proline-rich motif in this region plays a critical role in this signalling pathway(s). The present study may provide further insight into the mechanism of cellular responses mediated by IL-2 and other cytokines which utilize the IL-2Rgammac for their signal transmission. PMID: 10421845 [PubMed - indexed for MEDLINE] ---------------------------------------------------------------