No abstract

Alternative splicing in the central nervous system

A microarray analysis provides new evidence suggesting that specific cellular processes in the mammalian CNS are coordinated at the level of alternative splicing, and that a complex splicing code underlies CNS-specific alternative splicing regulation.

The challenges of effective vaccination against influenza are gaining more mainstream attention, as recent influenza seasons have reported low efficacy in annual vaccination programs worldwide. Combined with the potential emergence of novel influenza viruses resulting in a pandemic, the need for effective alternatives to egg-produced conventional vaccines has been made increasingly clear. DNA vaccines against influenza have been in development since the 1990s, but the initial excitement over success in murine model trials has been tempered by comparatively poor performance in larger animal models. In the intervening years, much progress has been made to refine the DNA vaccine platform—the rational design of antigens and expression vectors, the development of novel vaccine adjuvants, and the employment of innovative gene delivery methods. This review discusses how these advances have been applied in recent efforts to develop an effective influenza DNA vaccine.

CD28 is an accessory receptor that is involved in biological responses such as anergy, apoptosis, and cytokine production in T cells (13-16). The requirement for dual receptor ligation to activate the JNK cascade is unique for T cells and raises the important question of whether both receptors contribute to the JNK cascade, e.g. by activating a component that is shared by both receptor types. In this regard, it is known that both anti-CD3 and anti-CD28 mAbs induce GTP/GDP exchange on Ras (8, 17). Whereas Ras acts upstream of the JNK cascade in some receptor protein-tyrosine kinase signaling pathways, not all stimuli that activate JNKs in lymphocytes depend on Ras (18 -22). It is important to determine whether Ras is involved in the T cell response, because it provides us with a potential target by which to study the synergy between the TCR/CD3 and CD28 receptors in this cascade. The role of JNK in T cell activation is not well understood. Several lines of evidence suggest, however, that JNKs may be involved in inducing the transcriptional activation of AP-1 response elements in TCR-responsive genes (10). JNKs play a role in the expression as well as transcriptional activation of AP-1 binding proteins (19 -27). The JNK cascade leads to transcriptional activation of c-Jun by phosphorylation of serine residues (i.e. Ser 63 and Ser 73 ) in its transactivation domain (18, 28 -31). c-Jun, in turn, up-regulates its own expression by interacting with the c-Jun promoter (25, 31). In addition, JNKs up-regulate c-Fos expression by phosphorylation of the ternary complex factor, p62 TCF (Elk-1), which binds the c-fos promoter (23, 25). Both c-Fos and c-Jun contribute to the expression of the IL-2 gene, which, as for JNK activation, is dependent on co-ligation of CD3 and CD28 (10,16,32,33). This suggests that JNK may play a role in transcriptional activation of the IL-2 promoter. To this end, it is known that in the absence of CD28 co-stimulation, TCR ligation may lead to the induction of an-* This work was supported by United States Public Health Service Grants CA-09120 -21, GM41576, and AI-34567 (UCLA Asthma, Allergy and Immunologic Disease Center funded by the NIAID and NIEHS) and the Concern Foundation of Los Angeles. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.‡ To whom correspondence should be addressed: UCLA School of Medicine, Dept. of Medicine, CIA, 52-175 CHS, 10833 Le Conte Ave., Los Angeles, CA 1 The abbreviations used are: TCR, T cell receptor; ERK, extracellular signal-regulated kinase; JNK, c-Jun N-terminal kinase; MEKK-1, mitogen-activated protein kinase kinase kinase; TCF, ternary complex factor; AP-1, activating protein-1; NFAT, nuclear factor of activated T cells; PCR, polymerase chain reaction; RT-PCR, reverse transcription-PCR; mAb, monoclonal antibody; IL, interleukin; DA-MEKK-1 and DN-MEKK-1, dominant active and dominant ...

Signaling by the T-cell antigen receptor (TCR) involves both phospholipase C (PLC)-gamma 1 and p21ras activation. While failing to induce Shc/Grb2 association, ligation of the TCR/CD3 receptor in Jurkat T-cells induced hSos1-Grb2 complexes. In addition to hSos1, Grb2 participates in the formation of a tyrosine phosphoprotein complex that includes 145-, 95-, 70-, 54-, and 36-38-kDa proteins. p145 was identified as PLC-gamma 1 and p70 as the protein tyrosine kinase, ZAP-70. Although of the same molecular weight, p95 was not recognized by an anti-serum to p95 Vav. The SH2 domains of Grb2 and PLC-gamma 1 were required for the formation of this protein complex. In anti-CD3-treated cells, Grb2 redistributed from the cytosol to a particulate cell compartment along with p36/p38, ZAP-70, and PLC-gamma 1. Part of the Grb2 complex associated with the particulate compartment could be extracted with Nonidet P-40, while the rest was Nonidet P-40 insoluble. In both the detergent-soluble and -insoluble fractions, Grb2 coimmunoprecipitated with the zeta-chain of the TCR. Taken together, these results indicate that anti-CD3 induces Grb2-hSos1-PLC-gamma 1-p36/p38-ZAP70 complexes, which localize in the vicinity of TCR-zeta.