Urologic Oncology: Seminars and Original Investigations
Review articleReview article Alterations in cyclin D1, p53, and the cell cycle related elements: Implications for distinct genetic pathways of urinary bladder carcinogenesis
Section snippets
The mammalian cell cycle
The mammalian cell cycle has different phases in which specific molecular events occur (Fig. 1A): the G1 phase (gap 1), which spans from the end of mitosis to commencement of DNA synthesis; S phase (synthesis), when DNA replication occurs; G2 phase (gap 2), the period between the end of DNA synthesis and the beginning of mitosis; M phase (mitosis), when the cell physically divides into two daughter cells; and G0 phase (gap 0), when cells are in a quiescent state. Cell proliferation is
Functional consequences of cyclin D1 overexpression and the p16INK4A/cyclin D1/CDK4/Rb pathway
In eukaryotic cells, progression through the G1 phase of the cell cycle can be accelerated by the overproduction of G1 cyclins 19, 20, 21. Experimental overexpression of D-type cyclins in cell lines shortens the duration of G1, reduces the requirement for exogenous growth factors, and can prevent terminal differentiation [6]. Several lines of evidence indicate that cyclin D1, in association with CDK4, functions to phosphorylate Rb during the G1 phase of the cell cycle 12, 22. In its
Cell cycle and cancer
Cell cycle regulators exert their effects by governing cell cycle progression at various checkpoints and alterations in their expression are likely to contribute to tumorigenesis. In mammalian cells, progression of the cell cycle is strictly regulated by the restriction point, which is situated at the late G1 phase of the cell cycle. If the restriction point fails, deregulated growth and unrestricted cell cycling may lead to the development of cancer, because cancer is a disease characterized
Cyclin D1 as an oncogene
Among the members of the cyclin family, cyclin D1 was isolated as an oncogene and as a possible effector of mitogen-induced proliferation acting during the G1 phase of the cell cycle 10, 30. Numerous studies have suggested a cyclin D1 gene involvement in tumorigenesis. Initially implicated as an oncogene in a subset of parathyroid adenomas 11, 31, 32 and in B-cell lymphomas 33, 34, 35, cyclin D1 overexpression or gene amplification has been reported in human tumors of diverse histogenesis,
Cyclin D1 as an oncogene in urinary bladder carcinogenesis
Data from recent studies suggest that cyclin D1 gene amplification or overexpression represents a dominant oncogenic event in a subset of transitional cell carcinomas (TCCs) of the urinary bladder and may modify the evolution of a particular subset of these tumors. Cyclin D1 gene amplification [56] and mRNA and protein overexpression [1] have been reported in TCCs of the human urinary bladder. Cyclin D1 overexpression also has been observed in two-stage urinary bladder carcinogenesis in rats [2]
Genetic pathways in human urinary bladder carcinogenesis
It is clear that the development of a fully malignant tumor involves the progressive acquisition of mutations and epigenetic abnormalities in multiple genes [58]. Relatively detailed genetic pathways have been described for some tumors such as hereditary colorectal cancers 59, 60. Although the genetic alterations leading to urinary bladder carcinomas are less clearly formulated, several genetic pathways have been proposed for TCCs, which are the most common cancers of the lower urinary tract.
Animal models of urinary bladder carcinogenesis
Numerous urinary bladder carcinogenesis models have been developed using rats and mice; typically chemical carcinogens are administered in food or drinking water 75, 76, 77, 78, 79, 80, 81. Chemical carcinogens used in carcinogenesis experiments are generally divided into two categories: genotoxic carcinogens and nongenotoxic carcinogens. The most widely employed experimental protocols used for urinary bladder carcinogenesis in rats and mice are of two-stage or complete type. Rat two-stage
Genetic pathways of urinary bladder carcinogenesis in rats and mice
Models of urinary bladder carcinogenesis using rats and mice are useful for studies of the underlying molecular biology for several reasons. First, progression from preneoplastic lesions to carcinomas of increasing aggressiveness can be readily observed, thus allowing comparison of genetic events in precursor lesions with those in tumors. Second, stage specific molecular events in urinary bladder carcinogenesis can be readily analyzed in experimental systems using the multistage carcinogenesis
Mechanisms of cyclin D1 overexpression
The D-type cyclins have a very short half-life of approximately 30 minutes. Thus, overexpression of cyclin D1 protein in tumors can be due to either increased synthesis or reduced degradation. Several different mechanisms that may lead to overexpression of cyclin D1 protein in tumors have been proposed [115]; these include gene amplification of the cyclin D1 amplicon, translocation of cyclin D1 gene to the vicinity of a hyperactive promoter due to chromosomal rearrangements, transcriptional
Directions for future research
Although the detection of genetic alterations involved in the development of solid tumors using conventional molecular genetic studies of tumor DNA or RNA have been successful thus far, such molecular methods usually focus on LOH analysis of specific regions of chromosomes and mutation or expression of specific genes. The genetic alterations and alterations in mRNA expression profiles in solid tumors are likely to be numerous and a comprehensive evaluation using conventional methods is
Concluding remarks
In summary, data from recent studies support the hypothesis that overexpression of cyclin D1 is an activating oncogenic event in TCCs of the urinary bladder, possibly modifying the evolution of a particular subset of these tumors. Alterations of numerous cell cycle regulators, some of which have not been clearly characterized as oncogenes or tumor suppressor genes, have been determined in the rat bladder carcinogenesis models. It is important to examine in detail and to characterize the roles
Acknowledgements
We are thankful to our colleagues at the First Department of Pathology, Osaka City University Medical School: Drs. Shinji Yamamoto and Hideki Wanibuchi for thoughtful discussions, and Dr. Masuda Chikayoshi and Mr. Toshio Ichihara for expert technical assistance. We are also thankful to our collaborators at the Department of Urology, Osaka City University Medical School: Professor Taketoshi Kishimoto, Dr. Kazunobu Sugimura, Dr. Seiji Wada, Dr. Tatsuya Nakatani, Dr. Kweske Yamamoto, Dr. Shinichi
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