Cancer surveys最新文献

We summarize here a number of properties that have been described for G protein coupled membrane receptors. These concern structure-function relationship, regulation of expression and activity and linkage with pathology. The existence of subfamilies and subtypes is discussed in terms of evolution and selectivity. A comparison is made between binding sites for small ligands such as monoamines and larger ligands such as peptides and glycohormones. Cross-talk of G protein coupled receptors with receptor tyrosine kinase pathways is also discussed. Finally, the role of mutations in modulating receptor activity is evaluated with respect to human disease.

IL2 induces the proliferation of T lymphocytes through the IL2 receptor (IL2R) following T lymphocyte activation. The IL2R consists of at least three subunits, IL2R alpha, beta and gamma chains. The cytoplasmic regions of the IL2R beta and gamma chains are critical for transduction of the IL2 signal to the cell interior. Although IL2R beta and gamma chains lack an intrinsic protein tyrosine kinase (PTK) domain, these chains recruit various non-receptor type PTKs, such as p56lck (and other Src family PTKs), Jak PTKs and Syk PTKs. The recruited PTKs are then activated following ligand stimulation to invoke intracellular signalling for the cell proliferation. Furthermore, it has been demonstrated that the IL2R is linked to at least three distinct signalling pathways leading to the induction of the c-fos/c-jun genes, c-myc gene induction and bcl-2 gene induction. All these pathways are essential for IL2 mediated proliferative signalling and co-operate with each other to ensure a full scale signal transduction. These signalling pathways, except that for bcl-2 pathway, appear to be mediated by multiple PTKs: p56lck is critical for the induction of the c-fos/c-jun genes, the activation of Syk PTKs results in the induction of the c-myc gene and Jak3 PTK is required for the induction of both c-fos and c-myc genes. Finally, the IL2 system may serve as a prototype in understanding the pleiotropic function of cytokine receptors that lack intrinsic PTK domains; the cytoplasmic structures of these cytokine receptors have evolved to allow the combined action of different PTK family members (and other signalling molecules) expressed in different cell types, which may determine the activity of cytokines.

The Rho family of small GTP binding proteins play a key part in regulating the actin cytoskeleton and cell adhesion through integrin receptors. In addition, these proteins regulate signal transduction pathways essential for normal cell growth. Many of the molecules that regulate Rho have oncogenic activity, suggesting that members of the Rho family may have an important role in tumour formation.

The SAPKs represent novel conduits through which the effects of cellular insults or injury are transmitted to the nucleus to influence gene expression. The SAPK pathway consists of at least four levels of protein kinases that are activated by a wide range of agents that adversely affect cell growth. Unlike the structurally related MAPK pathway, the stress induced kinases are not required for mitogenesis and instead induce growth arrest. Given the modulation of the pathway by inflammatory cytokines, reperfusion injury and chemotherapeutics, determination of the physiological functions of the pathway may uncover new possibilities for diagnosis and therapeutic intervention.

Hydrolysis of PIP2 by specific PLC enzymes is involved in the regulation of different cellular processes by many extracellular signals. The need stringently to control this reaction is reflected by the fact that there are many PLC isozymes and multiple mechanisms linking these isozymes to various receptors. For two of the three PLC families found in mammalian cells (PLC beta and gamma), the components of the main regulatory pathways have been identified. PLC beta isozymes are regulated through G protein coupled receptors. Their activity is stimulated by interaction with alpha subunit from the Gq family and interaction with G protein beta gamma subunits. PLC gamma isozymes are regulated through receptor and non-receptor tyrosine kinases. The combination of SH2 dependent complex formation with phosphorylated tyrosine kinases and the subsequent phosphorylation of PLC gamma leads to stimulation of its activity. Although components that stimulate PLC beta and gamma isozymes have been identified, the molecular mechanism of stimulation remains largely unknown. Each signalling component operating within this general framework represents a family of related proteins. It is not clear what all the functional differences between members of the same family may be and to what extent they could determine specificity of individual signalling pathways. Similarly, it is not known to what extent alterations in PLC function/expression contribute to human pathologies. In the context of oncology, there is evidence for upregulation of PLC gamma in parallel with increased expression of the EGF receptor (Artega et al. 1991). However, it is not clear yet whether this is causally involved or a bystander effect.

The study of mutator strains of bacteria has elucidated new systems and pathways of mutagenesis and led to the defining of human counterparts to these systems. In addition to previous work that defined the mismatch repair system, newer studies have revealed a repair pathway for oxidative lesions, as well as demonstrating that mistranslation can increase mutation rates. Defects in the human repair pathways are involved in increased cancer susceptibility as well as a mutator character.

The identification of HRX and its partner genes is offering new insights into the genetic basis of the 11q23 leukaemias. Although some patterns and associations between the partner genes are beginning to emerge, it is not yet possible to frame a single unifying hypothesis for 11q23 leukaemic transformation. The study of transcriptional controls in other species, especially Drosophila and yeast, is offering possible clues as to the function of HRX and some of its partners. The identification of more partner genes may help to resolve these questions. The recognized poor prognosis of 11q23 leukaemias has prompted important variations in clinical trials. The molecular analysis of 11q23 events has therefore been particularly important in generating new molecular tools for the diagnosis and monitoring of disease in these patients. Ultimately, an understanding of 11q23 leukaemogenesis may open up new avenues for the molecular therapy of this disease.

This chapter has outlined our current understanding of the regulation of p70S6K activity and its importance for cell growth and proliferation. Although incomplete at the moment, the picture of P70S6K activation reveals novel mechanisms for mitogenic signalling that closely link lipid phosphorylation and protein activation in ways previously unrecognized. Knowledge about the regulation of this signalling pathway is already proving crucial for the medical management of patients. The p70S6K regulating pathways appear to be involved in cell transformation by the polyomavirus. Rapamycin is a strong candidate for use as an immunosuppressant and is currently being tested in clinical trials. Analysis of the activation of the proto-oncogene, akt, demonstrates a possible link of the p70S6K activating pathway to carcinogenesis. Equally exciting is the recent connection between the p70S6K regulating system and IGF2 expression, which may prove crucial for the treatment of IGF2 secreting rhabdomyosarcomas. Certainly, future work will fill in the gaps in our understanding and most likely provide more surprises in the fields of cell biology and molecular oncology.

Progression through the mammalian cell cycle requires the sequential activation of a series of cyclin dependent kinases. The activity of these kinases is regulated at several levels and the current challenge is to determine how the various signal transduction pathways are linked to the cell cycle machinery. An obvious focus is the so-called restriction point in late G1, and current evidence suggests that this is in part determined by the phosphorylation of the retinoblastoma protein (Rb) by the cyclin D dependent kinases, CDK4 and CDK6. Downstream targets of Rb, such as the E2F1 transcription factor, can promote cell cycle progression, whereas inhibitors of CDK4 and CDK6, such as p16CDKN2a, can block G1 progression. Many human tumours have been shown to have chromosomal abnormalities that directly affect components of this pathway, resulting in either the functional inactivation of p16 or Rb or the excessive activity of cyclin D1 or CDK4. Each of these lesions is likely to lead to unrestrained proliferation, and as they form part of a common pathway, they are generally mutually exclusive. Inhibitors of this pathway therefore have considerable promise as therapeutic agents.