抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

The selective degradation of many short-lived proteins in eukaryotic cells is carried out by the ubiquitin system. In this pathway, proteins are targeted for degradation by covalent ligation to ubiquitin, a highly conserved small protein. Ubiquitin-mediated degradation of regulatory proteins plays important roles in the control of numerous processes, including cell-cycle progression, signal transduction, transcriptional regulation, receptor down-regulation, and endocytosis. The ubiquitin system has been implicated in the immune response, development, and programmed cell death. Abnormalities in ubiquitin-mediated processes have been shown to cause pathological conditions, including malignant transformation. In this review we discuss recent information on functions and mechanisms of the ubiquitin system. Since the selectivity of protein degradation is determined mainly at the stage of ligation to ubiquitin, special attention is focused on what we know, and would like to know, about the mode of action of ubiquitin-protein ligation systems and about signals in proteins recognized by these systems.

The Ubiquitin System

http://web.stanford.edu/group/brunet/Cell1999

Akt Promotes Cell Survival by Phosphorylating and Inhibiting a Forkhead Transcription Factor

Mitogen-dependent progression through the first gap phase (G1) and initiation of DNA synthesis (S phase) during the mammalian cell division cycle are cooperatively regulated by several classes of cyclin-dependent kinases (CDKs) whose activities are in turn constrained by CDK inhibitors (CKIs). CKIs that govern these events have been assigned to one of two families based on their structures and CDK targets. The first class includes the INK4 proteins (inhibitors of CDK4), so named for their ability to specifically inhibit the catalytic subunits of CDK4 and CDK6. Four such proteins [p16 (Serrano et al. 1993), p15 (Hannon and Beach 1994), p18 (Guan et al. 1994; Hirai et al. 1995), and p19 (Chan et al. 1995; Hirai et al. 1995)] are composed of multiple ankyrin repeats and bind only to CDK4 and CDK6 but not to other CDKs or to D-type cyclins. The INK4 proteins can be contrasted with more broadly acting inhibitors of the Cip/Kip family whose actions affect the activities of cyclin D-, E-, and A-dependent kinases. The latter class includes p21 (Gu et al. 1993; Harper et al. 1993; El-Deiry et al. 1993; Xiong et al. 1993a; Dulic et al. 1994; Noda et al. 1994), p27 (Polyak et al. 1994a,b; Toyoshima and Hunter 1994), and p57 (Lee et al. 1995; Matsuoka et al. 1995), all of which contain characteristic motifs within their amino-terminal moieties that enable them to bind both to cyclin and CDK subunits (Chen et al. 1995, 1996; Nakanishi et al. 1995; Warbrick et al. 1995; Lin et al. 1996; Russo et al. 1996). Based largely on in vitro experiments and in vivo overexpression studies, CKIs of the Cip/Kip family were initially thought to interfere with the activities of cyclin D-, E-, and A-dependent kinases. More recent work has altered this view and revealed that although the Cip/Kip proteins are potent inhibitors of cyclin Eand A-dependent CDK2, they act as positive regulators of cyclin Ddependent kinases. This challenges previous assumptions about how the G1/S transition of the mammalian cell cycle is governed, helps explain some enigmatic features of cell cycle control that also involve the functions of the retinoblastoma protein (Rb) and the INK4 proteins, and changes our thinking about how either p16 loss or overexpression of cyclin D-dependent kinases contribute to cancer. Here we focus on the biochemical interactions that occur between CKIs and cyclin Dand E-dependent kinases in cultured mammalian cells, emphasizing the manner by which different positive and negative regulators of the cell division cycle cooperate to govern the G1-to-S transition. To gain a more comprehensive understanding of the biology of CDK inhibitors, readers are encouraged to refer to a rapidly emerging but already extensive literature (for review, see Elledge and Harper 1994; Sherr and Roberts 1995; Chellappan et al. 1998; Hengst and Reed 1998a; Kiyokawa and Koff 1998; Nakayama 1998; Ruas and Peters 1998).

/pdf/cdk-inhibitors-positive-and-negative-regulators-of-g1-phase-4awlfdse3n.pdf

CDK inhibitors: positive and negative regulators of G1-phase progression

Akt Phosphorylation of BAD Couples Survival Signals to the Cell-Intrinsic Death Machinery

A signaling pathway was delineated by which insulin-like growth factor 1 (IGF-1) promotes the survival of cerebellar neurons. IGF-1 activation of phosphoinositide 3-kinase (PI3-K) triggered the activation of two protein kinases, the serine-threonine kinase Akt and the p70 ribosomal protein S6 kinase (p70S6K). Experiments with pharmacological inhibitors, as well as expression of wild-type and dominant-inhibitory forms of Akt, demonstrated that Akt but not p70S6K mediates PI3-K-dependent survival. These findings suggest that in the developing nervous system, Akt is a critical mediator of growth factor-induced neuronal survival.

https://science.sciencemag.org/content/sci/275/5300/661.full.pdf

Regulation of Neuronal Survival by the Serine-Threonine Protein Kinase Akt

Nerve growth factor (NGF) induces both differentiation and survival of neurons by binding to the Trk receptor protein tyrosine kinase. Although Ras is required for differentiation, it was not required for NGF-mediated survival of rat pheochromocytoma PC-12 cells in serum-free medium. However, the ability of NGF to prevent apoptosis (programmed cell death) was inhibited by wortmannin or LY294002, two specific inhibitors of phosphatidylinositol (Pl)-3 kinase. Moreover, platelet-derived growth factor (PDGF) prevented apoptosis of PC-12 cells expressing the wild-type PDGF receptor, but not of cells expressing a mutant receptor that failed to activate Pl-3 kinase. Cell survival thus appears to be mediated by a Pl-3 kinase signaling pathway distinct from the pathway that mediates differentiation.

https://science.sciencemag.org/content/sci/267/5206/2003.full.pdf

Requirement for phosphatidylinositol-3 kinase in the prevention of apoptosis by nerve growth factor

Udžbenik sadrži cetiri dijela. I. obuhvaca stanicnu kemiju i osnove molekularne biologije ; II. se bavi protijekom hgeneticke informacije, III. strukturom i funkcijom stanice, bioenergetikom i metabolizmom, IV. stanicnom regulacijom, signalizacijom i stanicnim ciklusom s osvrtom na biomedicinsko znacenje

/pdf/the-cell-molecular-approach-3hsle8qxs4.pdf

The Cell : molecular approach

PART : INTRODUCTION. - An Overview of Cells and Cell Research - The Chemistry of Cells - Fundamentals of Molecular Biology - PART I1: THE FLOW OF GENETIC INFORMATION - The Organization and Sequences of Cellular Genomes - Replication, Maintenance, and Rearrangements of Genomic DNA - RNA Synthesis and Processing - Protein Synthesis, Processing, and Regulation - PART III: CELL STRUCTURE AND FUNCTION - The Nucleus - Protein Sorting and Transport: The Endoplasmic Reticulum, Golgi - Apparatus, and Lysosomes - Bioenergetics and Metabolism: Mitochondria, Chloroplasts, and - Peroxisomes - The Cytoskeleton and Cell Movement - The Cell Surface - PART IV CELL REGULATION - Cell Signaling - The Cell Cycle - Cancer -

Geoffrey M. Cooper

Papers

Regulation of Neuronal Survival by the Serine-Threonine Protein Kinase Akt

Requirement for phosphatidylinositol-3 kinase in the prevention of apoptosis by nerve growth factor

The Cell : molecular approach

The Cell: A Molecular Approach

Role of Glycogen Synthase Kinase-3 in the Phosphatidylinositol 3-Kinase/Akt Cell Survival Pathway