ISSN:0892-6638    

DOI:10.1096/fasebj.7.10.8344480

出版商:Wiley    

年代:1993

数据来源: WILEY

ISSN:0892-6638    

DOI:10.1096/fasebj.7.10.8344481

出版商:Wiley    

年代:1993

数据来源: WILEY

摘要:

Although the cloning of tumor suppressor genes has proved to be an arduous task, often involving several years of labor intensive cloning strategies, a greater understanding of neoplastic progression will be made once the function and role of these genes have been sorted out. To fully appreciate the state at which this field of research currently is, however, one must understand that the road to tumor suppression was paved by both somatic cell hybridization and chromosome transfer studies. Although regarded by many as laboratory artifact, somatic cell hybridization has provided strong circumstantial evidence, if not formal proof, for the existence of tumor suppressor genes. In further reducing the complexity associated with whole genome transfer, single chromosome transfer was subsequently developed as a refinement to this technique so that one could unequivocally correlate suppression with a particular chromosome. We have learned from these studies that single chromosomes harbor the genetic information necessary to reverse the malignant phenotype associated with cancer cells. Furthermore, multiple tumor suppressor loci are now known to exist, with one to several different loci associated with a given tumor type. In this review, we present evidence for tumor suppressor genes and discuss the early studies that led to their discovery.—Anderson, M. J., Stanbridge, E. J. Tumor suppressor genes studied by cell hybridization and chromosome transfer.FASEB J. 7:826‐833; 1993.

ISSN:0892-6638    

DOI:10.1096/fasebj.7.10.8344482

出版商:Wiley    

年代:1993

数据来源: WILEY

摘要:

Reversion of transformed cells provides biological system useful in multiple areas of cancer research. First, reversion can be induced by inhibiting the activities of specific oncogenes or replacing intact tumor suppressor genes, and such experiments yield important insights into the roles of these genes in carcinogenesis and normal growth regulation as well as the functional relationships between these genes and other known genes. Second, novel genes involved in growth regulation can be discovered by isolating revertants from transformed cells after mutagenesis or DNA transfection and then characterizing the genes responsible for the non‐transformed phenotype. Third, potential anti‐cancer drugs can be screened by reversion assay using cells transformed by specific oncogenes. The novel genes and chemicals discovered through these studies serve as valuable tools that help our understanding of how cells regulate their growth and differentiation.—Noda, M. Mechanisms of reversion.FASEB J. 7:834‐846; 1993.

ISSN:0892-6638    

DOI:10.1096/fasebj.7.10.8344483

出版商:Wiley    

年代:1993

数据来源: WILEY

摘要:

The retinoblastoma (RB) gene is the prototype tumor suppressor gene. It encodes a nuclear protein that acts as a cell cycle control checkpoint at the G1 phase. Deletion or inactivation of both RB alleles plays an essential, rate‐limiting role in retinoblastoma and in the osteosarcomas that arise within families that carry a mutated RB gene. RB inactivation is also found in other sarcomas, small cell carcinoma of the lung, and in carcinoma of the breast, bladder, and prostate. Transforming proteins encoded by SV40, and the transforming or tumor‐associated subtypes of adenoviruses and human papilloma viruses (HPV) can bind RB, thereby blocking its normal function. The EBNA‐5 protein of Epstein‐Barr virus (EBV) is also able to bind RB in vitro. In addition, RB can interact with several cellular proteins, including the transcription factor E2F. RB gene knock‐out mice die in utero around day 14 of gestation. The embryos show disturbed neural and hematopoietic differentiation, indicating that RB is vitally important for these processes. This notion is further supported by studies demonstrating that RB expression in mouse embryo tissues is highest in cells undergoing differentiation, and that RB is required for MyoD‐induced muscle differentiation.—Wiman, K. G. The retinoblastoma gene: role in cell cycle control and cell differentiation.FASEB J. 7:841‐845; 1993.

ISSN:0892-6638    

DOI:10.1096/fasebj.7.10.8393817

出版商:Wiley    

年代:1993

数据来源: WILEY

摘要:

Studies of retinoblastoma clearly identify mutation of theRB1gene on chromosome 13 as the primary cause of this cancer. However, all retinoblastoma tumors have an abnormal karyotype (1, 2) indicating the presence of additional mutations and suggesting that mutation of bothRB1alleles is insufficient for development of retinoblastoma. In addition, analysis ofRB1expression and ofRB1mutations in different tumors leads to the following dilemma: while theRB1gene product, p110RB1, is expressed in most dividing cells, germline mutations inactivating the function of p110RB1predispose primarily to retinoblastoma and to a lesser extent to osteosarcoma, but do not predispose to cancer in general. However, many tumors contain somatic mutations that disruptRB1function. Thus, we are faced with the unusual situation in which germline mutations in theRB1gene predispose to a very limited set of cancers, but somatic mutations inRB1appear to contribute to malignancy in many tissues. We propose that the role of theRB1gene is to maintain the cells in a stable, quiescent state required for terminal differentiation and that the effect ofRB1mutations in different tissues depends on the pattern of differentiation in that tissue. In tissues where differentiation follows a linear process from undifferentiated precursors to fully differentiated cells, loss ofRB1function during early stages of differentiation may lead to uncontrolled growth and the development of cancer. On the other hand, in cell renewal systems where cell number is usually maintained by a process of programmed cell death (PCD) or apoptosis, loss ofRB1function may lead to cell death.—Hamel, P. A., Phillips, R. A., Muncaster, M., Gallie, B. L. Speculations on the roles ofRB1in tissue‐specific differentiation, tumor initiation, and tumor progression.FASEB J. 7:846‐854; 1993.

ISSN:0892-6638    

DOI:10.1096/fasebj.7.10.8344484

出版商:Wiley    

年代:1993

数据来源: WILEY

摘要:

Tumorigenesis is characterized by a series of genetic alterations in both dominant oncogenes and tumor suppressor genes. A hallmark of tumor suppressor genes is that both alleles are generally altered during transformation, which usually represents a loss of function phenotype. The p53 tumor suppressor gene is the most frequently affected gene detected in human cancer. There is now growing evidence suggesting that mutation of p53 may involve not only a loss of function of wild‐type p53 activity but also a gain of function phenotype contributed by the mutant p53 protein. The study of the biological properties and functions of both wild‐type and mutant p53 is central to our understanding of human cancer. These properties and functions of wild‐type and mutant p53 will be compared and contrasted here and elsewhere within this thematic issue. In addition, the mechanisms of inactivation of p53 function, which include:1) mutation,2) inhibition by viral oncogene products,3) inhibition by cellular regulators, and4) alteration in subcellular localization, will be discussed.—Zambetti, G. P., Levine, A. J. A comparison of the biological activities of wild‐type and mutant p53.FASEB J. 7:855‐865; 1993.

ISSN:0892-6638    

DOI:10.1096/fasebj.7.10.8344485

出版商:Wiley    

年代:1993

数据来源: WILEY

摘要:

The oncogenic property of simian virus 40 depends in large part on the function of the virus‐coded T‐antigen. Although the precise mechanism of how T functions during neoplastic transformation is not clear, some answers to this question may lie in our understanding the nature of the proteins found to complex with T. The cellular protein p53 is perhaps the most extensively studied protein in this regard. Recently, p53 was defined as a growth suppressor protein. At about this same time, T was found to complex with another cell growth suppressor protein, the product of the retinoblastoma susceptibility gene. It has since become apparent that complex formation between these proteins affects their individual growth‐modulating activities. Quite often this alteration of activity correlates with an uncontrolled proliferative state of the cell. Thus, transformation by SV40 is thought to involve complex formation between the viral T oncoprotein and cellular growth suppressor proteins. This complex formation is believed to result in nullification of the growth suppressor protein properties, thus increasing the propensity of the cell toward uncontrolled growth, the hallmark of neoplastic transformation.—Ludlow, J. W. Interactions between SV40 large‐tumor antigen and the growth suppressor proteins pRB and p53.FASEB J. 7:866‐871; 1993.

ISSN:0892-6638    

DOI:10.1096/fasebj.7.10.8344486

出版商:Wiley    

年代:1993

数据来源: WILEY

摘要:

Human papillomaviruses (HPVs) contribute to the development of almost all cervical cancers, a common and often fatal human disease. The mechanisms by which the HPVs function in malignant progression appear to be related to the activity of the two viral oncoproteins, E6 and E7, which form complexes with several cell proteins normally involved in controlling cell growth. Of particular interest has been the association of E6 with p53 and E7 with Rb, both products of tumor suppressor genes. Expression of E6 and E7 is likely to overcome the regulation of cell proliferation normally mediated by proteins like p53 and Rb, allowing uncontrolled growth and providing the potential for malignant transformation. These activities of E6 and E7 support the importance of the tumor suppressor proteins in the maintenance of normal cell proliferation and provide novel approaches to understanding the mechanisms by which they function.—Vousden, K. Interactions of human papillomavirus transforming proteins with the products of tumor suppressor genes.FASEB J. 7:872‐879; 1993.

ISSN:0892-6638    

DOI:10.1096/fasebj.7.10.8393818

出版商:Wiley    

年代:1993

数据来源: WILEY

摘要:

The transforming gene products of the small DNA tumor viruses subvert host cell growth control mechanisms by binding to specific cell regulatory proteins. These include the retinoblastoma gene product (pRB) and p53. One indication of the pivotal roles played by these regulatory products is the observation that they are each targeted consistently by viruses of several groups, by adenoviruses, the human papillomaviruses, and the papovaviruses. In adenovirus, pRB and p53 are targeted by the E1A and E1B genes, respectively. The genetic probes made possible by manipulation of the virus genes in vitro have helped to illuminate the pathways in which pRB and p53 function. E1A studies have contributed to our current understanding that the retinoblastoma product is one of a family of related proteins, which with associated cycling and kinases can modulate the activity of the cellular E2F transcription factor. E1B studies have helped explore models of p53 function, including the suggestion that p53, probably through aspects of its transcription regulating activity, can initiate a pathway in which programmed cell death can be invoked to stop unrestricted cell proliferation.—Moran, E. Interaction of adenoviral proteins with pRB and p53.FASEB J. 7:880‐885; 1993.

ISSN:0892-6638    

DOI:10.1096/fasebj.7.10.8344487

出版商:Wiley    

年代:1993

数据来源: WILEY