Cancer Cell Cycles
06 Dec 1996-Science (American Association for the Advancement of Science)-Vol. 274, Iss: 5293, pp 1672-1677
TL;DR: Genetic alterations affecting p16INK4a and cyclin D1, proteins that govern phosphorylation of the retinoblastoma protein and control exit from the G1 phase of the cell cycle, are so frequent in human cancers that inactivation of this pathway may well be necessary for tumor development.
Abstract: Uncontrolled cell proliferation is the hallmark of cancer, and tumor cells have typically acquired damage to genes that directly regulate their cell cycles. Genetic alterations affecting p16(INK4a) and cyclin D1, proteins that govern phosphorylation of the retinoblastoma protein (RB) and control exit from the G1 phase of the cell cycle, are so frequent in human cancers that inactivation of this pathway may well be necessary for tumor development. Like the tumor suppressor protein p53, components of this "RB pathway," although not essential for the cell cycle per se, may participate in checkpoint functions that regulate homeostatic tissue renewal throughout life.
Citations
More filters
TL;DR: This work challenges previous assumptions about how the G1/S transition of the mammalian cell cycle is governed, helps explain some enigmatic features of cell cycle control that also involve the functions of the retinoblastoma protein (Rb) and the INK4 proteins, and changes the thinking about how either p16 loss or overexpression of cyclin D-dependent kinases contribute to cancer.
Abstract: Mitogen-dependent progression through the first gap phase (G1) and initiation of DNA synthesis (S phase) during the mammalian cell division cycle are cooperatively regulated by several classes of cyclin-dependent kinases (CDKs) whose activities are in turn constrained by CDK inhibitors (CKIs). CKIs that govern these events have been assigned to one of two families based on their structures and CDK targets. The first class includes the INK4 proteins (inhibitors of CDK4), so named for their ability to specifically inhibit the catalytic subunits of CDK4 and CDK6. Four such proteins [p16 (Serrano et al. 1993), p15 (Hannon and Beach 1994), p18 (Guan et al. 1994; Hirai et al. 1995), and p19 (Chan et al. 1995; Hirai et al. 1995)] are composed of multiple ankyrin repeats and bind only to CDK4 and CDK6 but not to other CDKs or to D-type cyclins. The INK4 proteins can be contrasted with more broadly acting inhibitors of the Cip/Kip family whose actions affect the activities of cyclin D-, E-, and A-dependent kinases. The latter class includes p21 (Gu et al. 1993; Harper et al. 1993; El-Deiry et al. 1993; Xiong et al. 1993a; Dulic et al. 1994; Noda et al. 1994), p27 (Polyak et al. 1994a,b; Toyoshima and Hunter 1994), and p57 (Lee et al. 1995; Matsuoka et al. 1995), all of which contain characteristic motifs within their amino-terminal moieties that enable them to bind both to cyclin and CDK subunits (Chen et al. 1995, 1996; Nakanishi et al. 1995; Warbrick et al. 1995; Lin et al. 1996; Russo et al. 1996). Based largely on in vitro experiments and in vivo overexpression studies, CKIs of the Cip/Kip family were initially thought to interfere with the activities of cyclin D-, E-, and A-dependent kinases. More recent work has altered this view and revealed that although the Cip/Kip proteins are potent inhibitors of cyclin Eand A-dependent CDK2, they act as positive regulators of cyclin Ddependent kinases. This challenges previous assumptions about how the G1/S transition of the mammalian cell cycle is governed, helps explain some enigmatic features of cell cycle control that also involve the functions of the retinoblastoma protein (Rb) and the INK4 proteins, and changes our thinking about how either p16 loss or overexpression of cyclin D-dependent kinases contribute to cancer. Here we focus on the biochemical interactions that occur between CKIs and cyclin Dand E-dependent kinases in cultured mammalian cells, emphasizing the manner by which different positive and negative regulators of the cell division cycle cooperate to govern the G1-to-S transition. To gain a more comprehensive understanding of the biology of CDK inhibitors, readers are encouraged to refer to a rapidly emerging but already extensive literature (for review, see Elledge and Harper 1994; Sherr and Roberts 1995; Chellappan et al. 1998; Hengst and Reed 1998a; Kiyokawa and Koff 1998; Nakayama 1998; Ruas and Peters 1998).
6,076 citations
Cites background from "Cancer Cell Cycles"
...…disruption of Rb or p16 function, or overexpression of cyclin D or CDK4, are common events in human cancer, complete loss of Cip/Kip function has not been observed, cyclin E amplification is rare, and gain-of-function mutations involving cyclin E have not been found (for review, see Sherr 1996)....
[...]
...Conversely, constitutive activation of the D cyclin pathway can reduce or overcome certain mitogen requirements for cell proliferation and thereby contribute to oncogenic transformation (for reviews, see Weinberg 1995; Sherr 1996; Bartkova et al. 1997)....
[...]
...…cyclin E–CDK2 becomes active and completes this process by phosphorylating Rb on additional sites (Matsushime et al. 1994; Meyerson and Harlow 1994; Mittnacht et al. 1994; Kitagawa et al. 1996; Ezhevsky et al. 1997; Lundberg and Weinberg 1998; for review, see Weinberg 1995; Sherr 1996; Taya 1997)....
[...]
TL;DR: Deregulated cell proliferation provides a minimal 'platform' necessary to support further neoplastic progression and should be targeted withroit targeting to have potent and specific therapeutic consequences.
Abstract: Beneath the complexity and idiopathy of every cancer lies a limited number of 'mission critical' events that have propelled the tumour cell and its progeny into uncontrolled expansion and invasion One of these is deregulated cell proliferation, which, together with the obligate compensatory suppression of apoptosis needed to support it, provides a minimal 'platform' necessary to support further neoplastic progression Adroit targeting of these critical events should have potent and specific therapeutic consequences
3,151 citations
Cites background from "Cancer Cell Cycles"
...Defects in this pathway, which may be universal in human cancers, include deletion of the RB gene itself and deregulation of the CDKs that phosphorylate and functionally inactivate pRB, either through direct over-activation of CDKs or through genetic loss of their inhibitor...
[...]
TL;DR: Increased beta-catenin levels may promote neoplastic conversion by triggering cyclin D1 gene expression and, consequently, uncontrolled progression into the cell cycle through a LEF-1 binding site in the cyclinD1 promoter.
Abstract: β-Catenin plays a dual role in the cell: one in linking the cytoplasmic side of cadherin-mediated cell–cell contacts to the actin cytoskeleton and an additional role in signaling that involves transactivation in complex with transcription factors of the lymphoid enhancing factor (LEF-1) family. Elevated β-catenin levels in colorectal cancer caused by mutations in β-catenin or by the adenomatous polyposis coli molecule, which regulates β-catenin degradation, result in the binding of β-catenin to LEF-1 and increased transcriptional activation of mostly unknown target genes. Here, we show that the cyclin D1 gene is a direct target for transactivation by the β-catenin/LEF-1 pathway through a LEF-1 binding site in the cyclin D1 promoter. Inhibitors of β-catenin activation, wild-type adenomatous polyposis coli, axin, and the cytoplasmic tail of cadherin suppressed cyclin D1 promoter activity in colon cancer cells. Cyclin D1 protein levels were induced by β-catenin overexpression and reduced in cells overexpressing the cadherin cytoplasmic domain. Increased β-catenin levels may thus promote neoplastic conversion by triggering cyclin D1 gene expression and, consequently, uncontrolled progression into the cell cycle.
2,261 citations
TL;DR: This work has shown that Cdk activity is governed by a complex network of regulatory subunits and phosphorylation events whose precise effects on Cdk conformation have been revealed by recent crystallographic studies.
Abstract: Cyclin-dependent kinases (Cdks) play a well-established role in the regulation of the eukaryotic cell division cycle and have also been implicated in the control of gene transcription and other processes. Cdk activity is governed by a complex network of regulatory subunits and phosphorylation events whose precise effects on Cdk conformation have been revealed by recent crystallographic studies. In the cell, these regulatory mechanisms generate an interlinked series of Cdk oscillators that trigger the events of cell division.
2,193 citations
TL;DR: Signal transduction pathways that transmit checkpoint signals in response to DNA damage, replication blocks, and spindle damage are revealed, underscoring the conservation of cell cycle regulatory machinery.
Abstract: Cell cycle checkpoints are regulatory pathways that control the order and timing of cell cycle transitions and ensure that critical events such as DNA replication and chromosome segregation are completed with high fidelity. In addition, checkpoints respond to damage by arresting the cell cycle to provide time for repair and by inducing transcription of genes that facilitate repair. Checkpoint loss results in genomic instability and has been implicated in the evolution of normal cells into cancer cells. Recent advances have revealed signal transduction pathways that transmit checkpoint signals in response to DNA damage, replication blocks, and spindle damage. Checkpoint pathways have components shared among all eukaryotes, underscoring the conservation of cell cycle regulatory machinery.
2,114 citations
References
More filters
Book•
01 Jan 1982
TL;DR: Part I: Molecular Biology of Cancer Molecular Methods in Oncology Section 1. Amplification Techniques Section 2. RNA Interference Section 3. cDNA arrays Section 4. Tissue arrays Section 5. Cytogenetics Section 6. Bioinformatics Genomics and Proteomics Molecular Targets in oncology.
Abstract: Part I: Molecular Biology of Cancer Molecular Methods in Oncology Section 1. Amplification Techniques Section 2. RNA Interference Section 3. cDNA arrays Section 4. Tissue arrays Section 5. Cytogenetics Section 6. Bioinformatics Genomics and Proteomics Molecular Targets in Oncology Section 1. Signal transduction systems Section 2. Cell cycle Section 3. Apoptosis Section 4. Telomerase Invasion and Metastases Angiogenesis Cancer Immunology Part II: Principles of Oncology Etiology of Cancer: Viruses Section 1. RNA Viruses Section 2. DNA Viruses Etiology of Cancer: Chemical Factors Etiology of Cancer: Tobacco Etiology of Cancer: Physical Factors Epidemiology of Cancer Section 1. Epidemiologic Methods Section 2. Cancer Statistics Principles of Surgical Oncology Section 1. General Issues Section 2. Laparascopic Surgery Principles of Radiation Oncology Principles of Medical Oncology Pharmacology of Cancer Chemotherapy Section 2. Pharmocokinetics Section 3. Pharmacogenomics Section 4. Alkylating Agents Section 5. Cisplatin and its Analogues Section 6. Antimetabolites Section 7. Topoisomerase Interactive Agents Section 8. Antimicrotubule Agents Section 9. Miscellaneous Chemotherapeutic Agents Pharmacology of Cancer Biotherapeutics Section 1. Interferon Section 2. Interleukin 2 Section 3. Histone deacetylase inhibitors as differentiation agents Section 4. Monoclonal Antibodies Pharmacology of Endocrine Manipulation Design and Analysis of Clinical Trials Part III: Practice of Oncology Cancer Prevention: Preventing Tobacco-Related Cancers Cancer Prevention: Diet and Chemopreventive Agents Section 1. Dietary fat Section 2. Dietary Fiber Section 3. Dietary fruits and vegetables: naturally occurring anticarcinogens Section 4. Retinoids, carotenoids and micronutrients Section 5. Dietary Carcinogens Section 6. Cyclo-oxygenase inhibitors Section 7. Physical Activity and Body Weight Cancer Prevention: Role of Surgery in Cancer Prevention Cancer Screening Advanced Molecular Diagnostics Advanced Imaging Methods Section 1. Functional and Metabolic Imaging Section 2. Interventional Radiology Cancer Diagnosis: Endoscopy Section 1. Gastrointestinal endoscopy Section 2. Respiratory Tract Cancer of the Head and Neck Section 1. Molecular Biology of Head and Neck Tumors Section 2. Treatment of Head and Neck Cancers Section 3. Rehabilitation after Treatment for Head Cancer of the Lung Section 1. Molecular Biology of Lung Cancer Section 2. Non-small Cell Lung Cancer Section 3. Small Cell Lung Cancer Neoplasms of the Mediastinum Cancers of the Gastrointestinal Tract
9,166 citations
TL;DR: A gene is identified, named WAF1, whose induction was associated with wild-type but not mutant p53 gene expression in a human brain tumor cell line and that could be an important mediator of p53-dependent tumor growth suppression.
8,339 citations
TL;DR: The p53 mutational spectrum differs among cancers of the colon, lung, esophagus, breast, liver, brain, reticuloendothelial tissues, and hemopoietic tissues as mentioned in this paper.
Abstract: Mutations in the evolutionarily conserved codons of the p53 tumor suppressor gene are common in diverse types of human cancer. The p53 mutational spectrum differs among cancers of the colon, lung, esophagus, breast, liver, brain, reticuloendothelial tissues, and hemopoietic tissues. Analysis of these mutations can provide clues to the etiology of these diverse tumors and to the function of specific regions of p53. Transitions predominate in colon, brain, and lymphoid malignancies, whereas G:C to T:A transversions are the most frequent substitutions observed in cancers of the lung and liver. Mutations at A:T base pairs are seen more frequently in esophageal carcinomas than in other solid tumors. Most transitions in colorectal carcinomas, brain tumors, leukemias, and lymphomas are at CpG dinucleotide mutational hot spots. G to T transversions in lung, breast, and esophageal carcinomas are dispersed among numerous codons. In liver tumors in persons from geographic areas in which both aflatoxin B1 and hepatitis B virus are cancer risk factors, most mutations are at one nucleotide pair of codon 249. These differences may reflect the etiological contributions of both exogenous and endogenous factors to human carcinogenesis.
8,063 citations
TL;DR: The hypothesis is developed that retinoblastoma is a cancer caused by two mutational events, in the dominantly inherited form, one mutation is inherited via the germinal cells and the second occurs in somatic cells.
Abstract: Based upon observations on 48 cases of retinoblastoma and published reports, the hypothesis is developed that retinoblastoma is a cancer caused by two mutational events. In the dominantly inherited form, one mutation is inherited via the germinal cells and the second occurs in somatic cells. In the nonhereditary form, both mutations occur in somatic cells. The second mutation produces an average of three retinoblastomas per individual inheriting the first mutation. Using Poisson statistics, one can calculate that this number (three) can explain the occasional gene carrier who gets no tumor, those who develop only unilateral tumors, and those who develop bilateral tumors, as well as explaining instances of multiple tumors in one eye. This value for the mean number of tumors occurring in genetic carriers may be used to estimate the mutation rate for each mutation. The germinal and somatic rates for the first, and the somatic rate for the second, mutation, are approximately equal. The germinal mutation may arise in some instances from a delayed mutation.
7,051 citations
TL;DR: In this article, an improved two-hybrid system was employed to isolate human genes encoding Cdk-interacting proteins (Cips) and found that CIP1 is a potent, tight-binding inhibitor of Cdks and can inhibit the phosphorylation of Rb by cyclin A-Cdk2.
5,726 citations