REFERENCE ABSTRACTS:
TITLE: CANCER CELL CYCLES
AUTHOR: CHARLES J. SHERR
JOURNAL: SCIENCE, VOL. 274, 12/6/96 [AXX60]
ABSTRACT: Uncontrolled cell proliferation is the hallmark of cancer. So many cancer cells share mutations affecting the p16INK4a and Cyclin D1 genes that the pathway regulated by these genes must be necessary for tumor development. This pathway probably plays an important role in regulating portion of the cell cycle.
The basic task of the cell cycle is to ensure that DNA is accurately replicated (copied) during S phase and that identical chromosomes are distributed equally to two daughter cells during M phase. The cell provides a number of checkpoints that act to protect the protein pathways that regulate the cell cycle. One would guess that damage to either the checkpoints or control genes themselves would have serious consequences to the cell. Scientists are studying these processes to determine the causes of cancer.
Oncogenic (cancer-causing) agent (chemicals, radiation, etc.) have their greatest effect by targeting regulators of the G1 phase. During the G1 phase, cells respond to extracellular signals by either starting another cell division cycle, or pulling back into a resting state. Mitogens (substances that stimulate mitosis - cell division) are needed by a cell in G1 phase to stimulate movement into the S phase. Normal cells use cytokines to control the effect of mitogens. Cancer cells abandon these controls.
The "decision" to divide occurs when cells pass a restriction point late in G1. After that point the cell becomes "deaf" to extracellular signals that control growth. Passage through the restriction point is controlled by cyclin-dependent kinases (CDKs). Of the more than 100 oncogenes (tumor causing genes) and tumor supressor genes that have been identified, all seem to focus on the 'machinery' controlling the cell's passage through G1 phase and checkpoint controls. The most frequently disrupted pathways are those controlled by the p53 and RB genes (p53 disruptions have been found in half of all cancers).
KEY WORDS/PHRASES
CELL CYCLE
CHECKPOINTS
CYCLIN-DEPENDENT KINASES (CDKS)
CYTOKINES
G1 PHASE
MITOGENS
ONCOGENES
RESTRICTION POINT
TUMOR SUPRESSOR GENES
TITLE: PROMISCUOUS CHROMOSOMAL PROTEINS: COMPLEXES ABOUT SEX
AUTHOR: MITZI I. KURODA and ANNE M. VILLENEUVE
JOURNAL: SCIENCE, VOL. 274, 12/6/96 [AXX61]
ABSTRACT: Chromosomes undergo dynamic structural changes as they move through the cell cycle. There is a mechanistic link between chromosome segregation and chromosome-specific gene regulation.
Studies of nematode worms show that the same proteins critical for X- chromosome replication also play a role in chromosome segregation in meiosis, implying that both processes are accomplished by the regulated condensation of chromosomes. The puzzling question is how the structural makeup of chromosomes controls the ability of a variety genes to be expressed at various times.
For most genes this task is accomplished through the creation of local domains of expression. These are defined areas (defined by, for example, concentrations of proteins which may inhibit gene function - the higher the concentration, the less gene function in the gene being controlled). With X chromosomes, however, there is an additional level of control.
Most species ensure that the expression of the X chromosome (activation of its gene leading to protein production) is equal between the sexes. Mammals do this by simply inactivating one X chromosome in each female cell. Nematode worms permit both X chromosomes to remain transcriptionally active (capable of producing protein products) but use a very fine type of control to partially repress both chromosomes. This process is remarkable because it involves a very subtle level of control that must be exercised over gene-controls of the many X-linked genes. The process is referred to as dosage compensation (think of the gene products as "doses" of proteins). Failure to turn on dosage compensation causes the death of males. This process is apparently related to chromosome condensation and a gene has been identified which is active in chromosome condensation and X-chromosome dosage compensation.
KEY WORDS/PHRASES
CHROMOSOME SEGREGATION
CONDENSATION OF CHROMOSOMES
DOSAGE COMPENSATION
LOCAL DOMAINS OF EXPRESSION
MEIOSIS
X-CHROMOSOME
TITLE: OPENING THE WAY TO GENE ACTIVITY
AUTHOR: ELIZABETH PENNISI
JOURNAL: SCIENCE, VOL. 275, 1/10/97 [AXX69]
ABSTRACT: In the cell nucleus, the DNA is arranged in nucleosomes, beadlike structures consisting of a DNA strand wrapped around a histone core and which are connected to each other by other histone molecules. Collectively, these make up the chromatin. A process known as "acetylation" is the key to unlocking the DNA from its tight embrace with histones, allowing it to become biologically active. Acetylation is clearly a fundamental cell regulatory process.
When acetyl molecules are bound to histone proteins, the histones hold DNA less tightly, allowing some degree of unraveling to occur. This permits other proteins to come into contact with the unraveled DNA which then leads to transcription, the "reading" of the genetic code segment carried by that piece of DNA. Four distinct acetylating enzymes have been discovered. To round out the picture, five enzymes have been discovered that reverse the acetylation process by removing acetyls from histones.
These enzymes have also been linked to gene expression and changes in cell growth. All four acetylating enzymes have turned out to be proteins already known to be associated with transcription factors. And, their activity has been linked to control of the cell cycle. Even slight changes in the acetylation process may lead to cancer.
The detective process that lead to the discovery of important role of acetylation in DNA regulation started with studies of the protozoan Tetrahymena and discovery of a HAT A gene which controlled this process. A similar gene (Gcn5p) was then found in yeast (eukaryotic cells) and, very recently, researchers reported discovered of related genes (PCAF, p300/CBP and TAFii230/250) in humans. In fact, TAFii230/250 is shared by fruit flies, yeast and man.
KEY WORDS/PHRASES
ACETYLATING ENZYMES
ACETYL MOLECULES
CELL CYCLE
GENE EXPRESSION
HISTONE PROTEINS
TRANSCRIPTION
TRANSCRIPTION FACTORS
TITLE: REGULATION OF CELL CYCLE SYNCHRONIZATION BY DECAPENTAPLEGIC DURING DROSOPHILA EYE DEVELOPMENT
AUTHOR: ANDREA PENTON, SCOTT B. SELLECK, F.MICHAEL HOFFMANN
JOURNAL: SCIENCE, VOL. 272, 1/10/97 [AXX71]
ABSTRACT: In the developing Drosophila eye, differentiation is coordinated with synchronized progression through the cell cycle. Signaling mediated by the transforming growth factor-ß-related gene decapentaplegic (dpp) was required for the synchronization of the cell cycle but not for cell fate specification. DPP may affect cell cycle synchronization by promoting cell cycle progression through the G2 - M phases. This synchronization is critical for the precise assembly of the eye.
The Drosophila eye has served as a model system for studying the genetic mechanisms the control the development of more complex tissues, including those of higher animals. The embryonic Drosophila eye develops from a single layer of epithelial cells known as the eye imaginal disc. The cell differentiation (specialization) process begins in the posterior end of the disc called the morphogenetic furrow (MF) and moves toward the anterior end. Inside the MF, cells differentiate into the highly ordered array of retinal cells and nonneural accessory cells that produce the ommatidia of the adult eye.
Differentiated cells posterior to the MF express the signaling protein hedghog (HH) which directs the anterior advancement of the furrow and activates the DPP gene. DPP controls cell fate determination in the developing wings and legs in response to HH.
Within the MF, cells divide in unison while outside of the MF cells divide randomly. Evidence suggests that the MF cell coordination is controlled by cyclin B, a mitotic cyclin which is required before mitosis can begin. As cells enter the late G2 phase of the cell cycle, cyclin B levels peak and then cyclin B degrades. After mitosis, cells arrest in the G1 phase in the MF and transcription of the dpp gene is activated. Researchers have identified the receptors which allow cells to respond to dpp proteins.
KEY WORDS/PHRASES
CELL DIFFERENTIATION
CELL FATE DETERMINATION
EPITHELIAL CELLS
EYE IMAGINAL DISC
MITOTIC CYCLIN
MODEL SYSTEM
SIGNALING PROTEIN