ISSN:0730-2312    

DOI:10.1002/jcb.240540402

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1994

数据来源: WILEY

摘要:

AbstractThe objective of this brief review is to stress the importance of multiple levels of molecular regulation of complex processes such as cell growth and to illustrate their derangements as they occur in cancer cells. One major research emphasis today is the regulation of transcription by binding of transactivating proteins to promoter motifs. Another focus is on the multiple roles of protein phosphorylations in signal transduction pathways. Evidence is strong, however, that major controls exist at numerous other molecular levels as well (Fig. 1). These include pre‐mRNA processing, pre‐mRNA degradation, mRNA degradation, control of translation, permanent protein modifications, protein degradation, reversible covalent protein alterations, noncovalent interactions with small molecules and with other proteins, and effects of relocations into cell compartments. These controls are exhibited in all biological processes. A few illustrative examples are briefly discussed, which come mainly from our researches in the area of cell cycle regulation and its derangement in can

ISSN:0730-2312    

DOI:10.1002/jcb.240540403

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1994

数据来源: WILEY

摘要:

AbstractA cell divides into two daughter cells by progressing serially through the precisely controlled G1, S, G2, and M phases of the cell cycle. The crossing of the G1/S border, which is marked by the initiation of DNA synthesis, represents commitment to division into two complete cells. Beyond this critical point no further external signals are required. We now have more comprehensive knowledge of the temporal sequence of systems at this key transition from G1to S—growth factor responses, a cascade of kinase reactions, activation of cyclins and their associated kinases, and oncogene and tumor suppressor gene products. Furthermore, we know that the absolute requirement for calcium and the timing of events associated with calmodulin and the 68 kDa calmodulin‐binding protein are consistent with overall Ca++/calmodulin control of all steps from the response to growth factors in G1to DNA replication in S phase. We now have to sort out the inter‐relationships of myriad control proteins and their relation to the Ca++/calmodulin‐dependent controls—Which are causes? Which are effects? And which are parallel processes? The answers will be important, as they represent both a much deeper understanding of this key process of life and an important opportunity for improving therapeutic

ISSN:0730-2312    

DOI:10.1002/jcb.240540404

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1994

数据来源: WILEY

摘要:

AbstractThymidylate synthase (TS) is an essential enzyme that catalyzes the formation of thymidylic acid in the de novo biosynthetic pathway and is the target enzyme for a variety of chemotherapeutic agents. The TS gene is expressed at a much higher level in proliferating cells than in quiescent cells. Control is primarily exerted at the posttranscriptional level. Studies with chimeric TS minigenes have shown that regulation of TS mRNA content in growth‐stimulated mouse fibroblasts requires the presence of sequences located upstream of the essential promoter elements. In addition, an efficiently spliced intron must be present within the transcript. Neither sequence by itself is sufficient for proper regulation, suggesting that the upstream and downstream sequences may communicate to effect regulation. A possible mechanism by which the upstream sequences influence the efficiency of splicing of TS transcripts in a cell cycle specific manner is described.Expression of the human TS gene is also controlled at the translational level. The TS enzyme is able to block the translation of its own mRNA by binding to the message in the vicinity of the AUG start codon. The translational block is relieved in the presence of substrates or inhibitors of the enzyme. The autogenous translational regulation of TS mRNA is likely to be responsible for the rapid increase in TS enzyme level that occurs when cells are exposed to certain TS inhibitors. Elucidation of the mechanism by which the translational control is exerted may lead to the design of more effective TS inhibitor

ISSN:0730-2312    

DOI:10.1002/jcb.240540405

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1994

数据来源: WILEY

摘要:

AbstractHistone gene expression is restricted to the S‐phase of the cell cycle. Control is at multiple levels and is mediated by the integration of regulatory signals in response to cell cycle progression and the onset of differentiation. The H4 gene promoter is organized into a series of independent and overlapping regulatory elements which exhibit selective, phosphorylation‐dependent interactions with multiple transactivation factors. The three‐dimensional organization of the promoter and, in particular, its chromatin structure, nucleosome organization, and interactions with the nuclear matrix may contribute to interrelationships of activities at multiple promoter elements. Molecular mechanisms are discussed that may participate in the coordinate expression of S‐phase‐specific core and H1 histone genes, together with other genes functionally coupled with DNA re

ISSN:0730-2312    

DOI:10.1002/jcb.240540406

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1994

数据来源: WILEY

摘要:

AbstractA number of cell culture model systems have been used to study the regulation of cell cycle progression at the molecular level. In this paper we describe the WI‐38 cell long‐term quiescence model system. By modulating the length of time that WI‐38 cells are density arrested, it is possible to proportionately alter the length of the prereplicative or G‐1 phase which the cell traverses after growth factor stimulation in preparation for entry into DNA synthesis. Through studies aimed at understanding the cause and molecular nature of the prolongation of the prereplicative phase, we have determined that gene expression plays an important role in establishing growth factor “competence” and that once the cell becomes “competent” there is a defined order to the molecular events that follow during the remainder of G‐1. More specifically, we have determined that the prolongation represents a delay in the ability of long term quiescent cells to become fully “competent” to respond to growth factors which regulate progression through G‐1 into S. This prolongation appears to occur as a result of changes during long term quiescence in the ability of immediate early G‐1 specific genes (such as c‐myc) to activate the expression of early G‐1 specific genes (such as ornithine decarboxylase). While ODC is the first and thus far only growth associated gene identified as a target of c‐myc (and the Myc/Max protein complex), it is likely that further studies in this model system will reveal other early G‐1 growth regulatory genes. We anticipate that future follow‐up studies in this model system will provide additional valuable information abuot the function of growth‐regulatory genes in controlling growth factor resp

ISSN:0730-2312    

DOI:10.1002/jcb.240540407

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1994

数据来源: WILEY

摘要:

AbstractSerpentine receptors coupled to the heterotrimeric G protein, Gi2, are capable of stimulating DNA synthesis in a variety of cell types. A common feature of the Gi2‐coupled stimulation of DNA synthesis is the activation of the mitogen‐activated protein kinases (MAPKs). The regulation of MAPK activation by the Gi2‐coupled thrombin and acetylcholine muscarinic M2receptors occurs by a sequential activation of a network of protein kinases. The MAPK kinase (MEK) which phosphorylates and activates MAPK is also activated by phosphorylation. MEK is phosphorylated and activated by either Raf or MEK kinase (MEKK). Thus, Raf and MEKK converge at MEK to regulate MAPK. Gi2‐coupled receptors are capable of activating MEK and MAPK by Raf‐dependent and Raf‐independent mechanisms. Pertussis toxin catalyzed ADP‐ribosylation of αi2inhibits both the Raf‐dependent and‐independent pathways activated by Gi2‐coupled receptors. The Raf‐dependent pathway involves Ras activation, while the Raf‐independent activation of MEK and MAPK does not involve Ras. The Raf‐independent activation of MEK and MAPK most likely involves the activation of MEKK. The vertebrate MEKK is homologous to the Ste11 and Byr2 protein kinases in the yeastSaccharomyces cerevisiaeandSchizosaccharomyces pombe, respectively. The yeast Ste11 and Byr2 protein kinases are involved in signal transduction cascades initiated by pheromone receptors having a 7 membrane spanning serpentine structure coupled to G proteins. MEKK appears to be conserved in the regulation of G protein‐coupled signal pathways in yeast and vertebrates. Raf represents a divergence in vertebrates from the yeast pheromone‐responsive protein kinase system. Defining MEKK and Raf as a divergence in the MAPK regulatory network provides a mechanism for differential regulation of this system by Gi2‐coupled receptors as well as other receptor systems

ISSN:0730-2312    

DOI:10.1002/jcb.240540408

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1994

数据来源: WILEY

摘要:

AbstractThe H1 family is the most divergent subgroup of the highly conserved class of histone proteins [Cole: Int J Pept Protein Res 30:433–449, 1987]. In several vertebrate species, the H1 complement comprises five or more subtypes, and tissue specific patterns of H1 histones have been described. The diversity of the H1 histone family raises questions about the functions of different H1 subtypes and about the differential control of expression of their genes. The expression of main type H1 genes is coordinated with DNA replication, whereas the regulation of synthesis of replacement H1 subtypes, such as H1° and H5, and the testis specific H1t appears to be more complex. The differential control of H1 gene expression is reflected in the chromosomal organization of the genes and in different promoter structures. This review concentrates on a comparison of the chromosomal organization of main type and replacement H1 histone genes and on the differential regulation of their expression. General structural and functional data, which apply to both H1 and core histone genes and which are covered by recent reviews, will not be discussed in deta

ISSN:0730-2312    

DOI:10.1002/jcb.240540409

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1994

数据来源: WILEY

摘要:

AbstractWe have characterized a nuclear phosphoprotein of 57 kda, statin, found only in nonproliferating cells of both quiescent and senescent natures. Emerging results suggest that statin may function as a sequester to block the early G1phase phosphorylation for the RB protein. A second protein, terminin, undergoes senescence‐specific posttranslational modification from 90 to 60 kda, and further death‐specific conversion from 60 to 30 kda. We also found that apoptotic mouse 3T3 fibroblasts express c‐fos, c‐myc, c‐jun, andcdc2, as well as the upregulation of RB phosphorylation and BrdU incorporation, just before final DNA fragmentation and death. It seems that en route to death, cells re‐enter the cell‐cycle traverse and experience early G1and part of S Phase; however, this cycling event is an abortive one. In contrast, senescent fibroblasts are resistant to the initiation of the death program, since they are unable to enter cell cycle traverse. Long‐term serial passaging of normal human fibroblasts may be inadvertently selecting those, while termed as senescent, are also specialized survivors, and thus a good culture model to study both the control of permanent departure from cell cycle traverse and the mechanism underlying the survival or antideath c

ISSN:0730-2312    

DOI:10.1002/jcb.240540410

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1994

数据来源: WILEY

摘要:

AbstractAs detailed information accumulates about how cell cycle events are regulated, we can expect new opportunities for application to cancer therapy. The altered expression of oncogenes and tumor suppressor genes that commonly occurs in human cancers may impair the ability of the cells to respond to metabolic perturbations or stress. Impaired cell cycle regulation would make cells vulnerable to pharmacologic intervention by drug regimens tailored to the defects existing in particular tumors. Recent findings that may become applicable to therapy are reviewed, and the possible form of new therapeutic stratagems is considered.

ISSN:0730-2312    

DOI:10.1002/jcb.240540411

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1994

数据来源: WILEY