Review article
Review article Alterations in cyclin D1, p53, and the cell cycle related elements: Implications for distinct genetic pathways of urinary bladder carcinogenesis

https://doi.org/10.1016/S1078-1439(98)00033-7Get rights and content

Abstract

Data from recent studies support the hypothesis that overexpression of cyclin D1 acts as an oncogenic event during development of transitional cell carcinomas of urinary bladder, possibly modifying the evolution of a particular subset of these tumors. We recently described overexpression of cyclin D1 and alteration in other cell cycle related elements in chemical carcinogenesis of the rat urinary bladder. Here, we discuss in more detail the implications of these changes for pathways of urinary bladder neoplasia.

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

References (128)

  • C.C.R. Lee et al.

    Significance of cyclin D1 overexpression in transitional cell carcinomas of the urinary bladder and its correlation with histopathologic features

    Cancer (Phila)

    (1997)
  • C.C.R. Lee et al.

    Cyclin D1 overexpression in rat two-stage bladder carcinogenesis and its relationship with oncogenes, tumor suppressor genes, and cell proliferation

    Cancer Res

    (1997)
  • T. Hunter et al.

    Cyclins and cancer IIcyclin D and CDK inhibitors come of age

    Cell

    (1994)
  • M. Serrano et al.

    A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D1/CDK4

    Nature (Lond)

    (1993)
  • G.J. Hannon et al.

    p15INK4B is a potential effector of TGF-β-induced cell cycle arrest

    Nature (Lond)

    (1994)
  • C.J. Sherr et al.

    Inhibitors of mammalian G1 cyclin-dependent kinases

    Genes Dev

    (1995)
  • C.J. Sherr

    Mammalian G1 cyclins

    Cell

    (1993)
  • C.J. Sherr

    D-type cyclins

    Trends Biochem Sci

    (1995)
  • A.B. Pardee

    G1 events and regulation of cell proliferation

    Science (Washington DC)

    (1989)
  • H. Matsushime et al.

    Colony-stimulating factor I regulates novel cyclins during the G1 phase of the cell cycle

    Cell

    (1991)
  • T. Motokura et al.

    A novel cyclin encoded by a bcl-linked candidate oncogene

    Nature (Lond)

    (1991)
  • R.A. Weinberg

    The retinoblastoma protein and cell cycle control

    Cell

    (1995)
  • H. Matsushime et al.

    D-type cyclin-dependent kinase activity in mammalian cells

    Mol Cell Biol

    (1994)
  • S.F. Dowdy et al.

    Physical interactions of the retinoblastoma protein with human cyclins

    Cell

    (1993)
  • X. Grana et al.

    Cell cycle control in mammalian cellsrole of cyclins, cyclin-dependent kinases, growth suppressor genes, and cyclin-dependent kinase inhibitors

    Oncogene

    (1995)
  • J. Nevins

    Cell cycle targets of the DNA tumor viruses

    Curr Opin Genet Dev

    (1994)
  • G.J. Hanon et al.

    Isolation of the Rb-related p130 through its interaction with CDK2 and cyclins

    Genes Dev

    (1993)
  • M.E. Ewen et al.

    Molecular cloning, chromosomal mapping, and expression of the cDNA for p107, a retinoblastoma gene product-related protein

    Cell

    (1991)
  • M. Ohtsubo et al.

    Cyclin-dependent regulation of G1 in mammalian fibroblasts

    Science (Washington DC)

    (1993)
  • D.E. Quelle et al.

    Overexpression of mouse D-type cyclins accelerates G1 phase in rodent fibroblasts

    Genes Dev

    (1993)
  • D. Resnitzky et al.

    Acceleration of the G1/S phase transition by expression of cyclins D1 and E with an inducible system

    Mol Cell Biol

    (1994)
  • D. Resnitzky et al.

    Different roles for cyclins D1 and E in regulation of the G1-to-S transition

    Mol Cell Biol

    (1995)
  • A. Okamoto et al.

    Mutations and altered expression of p16INK4A in human cancer

    Proc Natl Acad Sci USA

    (1994)
  • W. Jiang et al.

    Altered expression of the cyclin D1 and retinoblastoma genes in human esophageal cancer

    Proc Natl Acad Sci USA

    (1993)
  • G.I. Shapiro et al.

    Reciprocal Rb inactivation and p16INK4 expression in primary lung cancers and cell lines

    Cancer Res

    (1995)
  • J. He et al.

    Lack of p16INK4 or retinoblastoma protein (pRb), or amplification-associated overexpression of cdk4, is observed in distinct subsets of malignant glial tumors and cell lines

    Cancer Res

    (1995)
  • K. Ueki et al.

    CDKN2/p16 or RB alterations occur in the majority of glioblastomas and are inversely correlated

    Cancer Res

    (1996)
  • T. Yeager et al.

    Increased p16 levels correlate with pRb alterations in human urothelial cells

    Cancer Res

    (1995)
  • J. Lukas et al.

    Cyclin D1 is dispensable for G1 control in retinoblastoma gene-deficient cells independently of cdk4 activity

    Mol Cell Biol

    (1995)
  • Y. Xiong et al.

    Human D-type cyclin

    Cell

    (1991)
  • A. Arnold et al.

    Molecular cloning and chromosomal mapping of DNA rearranged with the parathyroid hormone gene in a parathyroid adenoma

    J Clin Invest

    (1989)
  • C.L. Rosenberg et al.

    Rearrangement and overexpression of D11S287E, a candidate oncogene on chromosome 11q13 in benign parathyroid tumors

    Oncogene

    (1991)
  • D.A. Withers et al.

    Characterization of a candidate bcl-1 gene

    Mol Cell Biol

    (1991)
  • M. Seto et al.

    Gene rearrangement and overexpression of PRAD1 in lymphoid malignancy with t(11;14)(q13;q32) translocation

    Oncogene

    (1992)
  • C.J. de Boer et al.

    Multiple breakpoints within the BCL-1 locus in B-cell lymphomarearrangements of the cyclin D1 gene

    Cancer Res

    (1993)
  • W. Jiang et al.

    Amplification and expression of the human cyclin D gene in esophageal cancer

    Cancer Res

    (1992)
  • H. Naitoh et al.

    Overexpression and localization of cyclin D1 mRNA and antigen in esophageal cancer

    Am J Pathol

    (1995)
  • J.R. Berenson et al.

    Frequent amplification of the bcl-1 locus in head and neck squamous cell carcinomas

    Oncogene

    (1989)
  • T. Callender et al.

    PRAD-1 (CND1)/cyclin D1 oncogene amplification in primary head and neck squamous cell carcinoma

    Cancer (Phila)

    (1994)
  • J. Bartkova et al.

    Abnormal patterns of D-type cyclin expression and G1 regulation in head and neck cancer

    Cancer Res

    (1995)
  • S.Y. Zhang et al.

    Immunohistochemistry of cyclin D1 in human breast cancer

    Am J Clin Pathol

    (1994)
  • G.G. McIntosh et al.

    Determination of the prognostic value of cyclin D1 overexpression in breast cancer

    Oncogene

    (1995)
  • N. Nishida et al.

    Amplification and overexpression of the cyclin D1 gene in aggressive human hepatocellular carcinoma

    Cancer Res

    (1994)
  • D.C. Betticher et al.

    Prognostic significance of CCND1 (cyclin D1) overexpression in primary resected non-small-cell lung cancer

    Br J Cancer

    (1996)
  • C.C.R. Lee et al.

    Assessment of cell cycle related elements p53, p21WAF1/Cip1, cyclin D1 and PCNA in a mixed transitional cell carcinoma and adenocarcinoma of the renal pelvisa case report

    Jpn J Clin Oncology

    (1998)
  • W. Jiang et al.

    Overexpression of cyclin D1 in rat fibroblasts causes abnormalities in growth control, cell cycle progression and gene expression

    Oncogene

    (1993)
  • T.C. Wang et al.

    Mammary hyperplasia and carcinoma in MMTV-cyclin D1 (PRAD-1) transgenic mice

    Nature (Lond)

    (1994)
  • H. Nakagawa et al.

    The targeting of the cyclin D1 oncogene by an Epstein-Barr virus promoter in transgenic mice causes dysplasia in the tongue, esophagus and forestomach

    Oncogene

    (1997)
  • A. Mueller et al.

    A transgenic mouse model with cyclin D1 overexpression results in cell cycle, epidermal growth factor receptor, and p53 abnormalities

    Cancer Res

    (1997)
  • A.B. Bianchi et al.

    Overexpression of cyclin D1 in mouse skin carcinogenesis

    Oncogene

    (1993)
    • View full text
    Copyright © 1999 Elsevier Science Inc. All rights reserved.