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Understanding the Biology of Cancer
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REVIEW
Apoptosis, an evolutionarily conserved form of cell suicide, requires specialized machinery. The central component of this
machinery is a proteolytic system involving a family of proteases called caspases. These enzymes participate in a cascade
that is triggered in response to proapoptotic signals and culminates in cleavage of a set of proteins, resulting in disassembly
of the cell. Understanding caspase regulation is intimately linked to the ability to rationally manipulate apoptosis for therapeutic
gain.
The progression of a cell through the cell cycle is promoted by cyclin dependent kinases (CDKs), which are positively regulated by cyclins and negatively regulated by CDK inhibitors. D type cyclins interact with CDK4 and CDK6 to drive the progression of a cell through early/mid-G(1)in response to mitogen stimulation. The association of cyclin E with CDK2 forms an active complex in late G(1) that directs entry into S-phase. S-phase progression is directed by the cyclin A/CDK2 complex, and the complex of cyclin A with Cdc2 (also known as CDK1) is important for G(2) phase. Lastly, cyclin B/CDK1 complex is necessary for the entry into mitosis. To date only one class of substrates have been identified for cyclinD-CDK4 and -CDK6 complexes, those belonging to pRb family of proteins, whereas the list of cyclin E-CDK2 substrates continues to lengthen. The tight regulation of cyclin E both at the transcriptional level and by ubiquitin-mediated proteolysis indicates that it has a major role for the control of G(1)/S transition. The recent identification of key substrates for cyclin E-CDK2 complex has increased our appreciation of how cyclin E overexpression seen in many human cancers can lead to genomic instability, a feature that leads the tumor to a more aggressive state. In breast cancer, the identification of low molecular weight (LMW) forms of cyclin E generated specifically in tumors due to elastase mediated amino-terminal proteolytic processing opens new possibilities for a targeted treatment of breast cancer. These truncated forms of cyclin E have an increased cyclin E-CDK2 kinase activity, which correlates in vivo with accelerated entry into S phase. Characterization of the biochemical properties of these LMW forms of cyclin E, in terms of substrate specificity, extent of their inhibition by the CDK inhibitors of the Cip/Kip family, their sensitivity to degradation, as well as elucidating their biological activities in the whole animal, should help us to better understand their role in breast cancer oncogenesis and help provide novels agents to target them.
Each day, approximately 50 to 70 billion cells perish in the average adult because of programmed cell death (PCD). Cell death in self-renewing tissues, such as the skin, gut, and bone marrow, is necessary to make room for the billions of new cells produced daily. So massive is the flux of cells through our bodies that, in a typical year, each of us will produce and, in parallel, eradicate a mass of cells equal to almost our entire body weight. The morphologic ritual cells go through when experiencing PCD has been termed apoptosis and is executed by a family of intracellular proteases, called caspases. Unlike accidental cell deaths caused by infarction and trauma, these physiologic deaths culminate in fragmentation of cells into membrane-encased bodies which are cleared through phagocytosis by neighboring cells without inciting inflammatory reactions or tissue scarring. Defects in the processes controlling PCD can extend cell life span, contributing to neoplastic cell expansion independently of cell division. Moreover, failures in normal apoptosis pathways contribute to carcinogenesis by creating a permissive environment for genetic instability and accumulation of gene mutations, promoting resistance to immune-based destruction, allowing disobeyance of cell cycle checkpoints that would normally induce apoptosis, facilitating growth factor/hormone–independent cell survival, supporting anchorage-independent survival during metastasis, reducing dependence on oxygen and nutrients, and conferring resistance to cytotoxic anticancer drugs and radiation. Elucidation of the genes that constitute the core machinery of the cell death pathway has provided new insights into tumor biology, revealing novel strategies for combating cancer.
HOW external growth signals are transmitted from the surface of the cell to the nucleus is one of the fundamental problems of cell biology. Research in the field of signal transduction has been motivated by the assumption that understanding the signal pathways responsible for cell growth will yield insight into the uncontrolled growth seen in cancer. Recently, this assumption has been supported by the discovery that many oncogenes are altered versions of the normal genes that control cell growth.1 2 3 These genes, implicated in the process of oncogenesis, encode proteins that function at every level of growth regulation. On encountering a . . .
The events of the cell cycle of most organisms are ordered into dependent pathways in which the initiation of late events
is dependent on the completion of early events. In eukaryotes, for example, mitosis is dependent on the completion of DNA
synthesis. Some dependencies can be relieved by mutation (mitosis may then occur before completion of DNA synthesis), suggesting
that the dependency is due to a control mechanism and not an intrinsic feature of the events themselves. Control mechanisms
enforcing dependency in the cell cycle are here called checkpoints. Elimination of checkpoints may result in cell death, infidelity
in the distribution of chromosomes or other organelles, or increased susceptibility to environmental perturbations such as
DNA damaging agents. It appears that some checkpoints are eliminated during the early embryonic development of some organisms;
this fact may pose special problems for the fidelity of embryonic cell division.
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We wish to thank Terry Schoop of Biomed Arts Associates, San Francisco, for preparation of the figures, Cori Bargmann and Zena Werb for insightful comments on the manuscript, and Normita Santore for editorial assistance. In addition, we are indebted to Joe Harford and Richard Klausner, who allowed us to adapt and expand their depiction of the cell signaling network, and we appreciate suggestions on signaling pathways from Randy Watnick, Brian Elenbas, Bill Lundberg, Dave Morgan, and Henry Bourne. R. A. W. is a Ludwig Foundation and American Cancer Society Professor of Biology. His work has been supported by the Department of the Army and the National Institutes of Health. D. H. acknowledges the support and encouragement of the National Cancer Institute. Editorial policy has rendered the citations illustrative but not comprehensive.
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.
As formulated in 1974, the concept of the restriction point of the cell cycle was based on cell biological experiments, yet allowing accurate molecular predictions and spurring a search for the restriction factor. Although cyclin D meets the criteria of the R-factor, the picture as outlined here is more interesting and far more complex. We discuss the relationship between the restriction knot and DNA damage-checkpoints. Finally, we discuss how loss of the restriction point in cancer leads to loss of checkpoint control and to insensitivity to antimitogens including some mechanism-based anticancer therapeutics.
Key Words:
Cell cycle, Cyclins, Growth factors, Oncogenes
Cyclin-dependent kinases (cdks) are critical regulators of cell cycle progression and RNA transcription. A variety of genetic and epigenetic events cause universal overactivity of the cell cycle cdks in human cancer, and their inhibition can lead to both cell cycle arrest and apoptosis. However, built-in redundancy may limit the effects of highly selective cdk inhibition. Cdk4/6 inhibition has been shown to induce potent G1 arrest in vitro and tumor regression in vivo; cdk2/1 inhibition has the most potent effects during the S and G2 phases and induces E2F transcription factor-dependent cell death. Modulation of cdk2 and cdk1 activities also affects survival checkpoint responses after exposure to DNA-damaging and microtubule-stabilizing agents. The transcriptional cdks phosphorylate the carboxy-terminal domain of RNA polymerase II, facilitating efficient transcriptional initiation and elongation. Inhibition of these cdks primarily affects the accumulation of transcripts with short half-lives, including those encoding antiapoptosis family members, cell cycle regulators, as well as p53 and nuclear factor-kappa B-responsive gene targets. These effects may account for apoptosis induced by cdk9 inhibitors, especially in malignant hematopoietic cells, and may also potentiate cytotoxicity mediated by disruption of a variety of pathways in many transformed cell types. Current work is focusing on overcoming pharmacokinetic barriers that hindered development of flavopiridol, a pan-cdk inhibitor, as well as assessing novel classes of compounds potently targeting groups of cell cycle cdks (cdk4/6 or cdk2/1) with variable effects on the transcriptional cdks 7 and 9. These efforts will establish whether the strategy of cdk inhibition is able to produce therapeutic benefit in the majority of human tumors.