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CELL CYCLE AND CELL DIVISION | Lead Editor: Zhaohua Tang, Ivor Hickey
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New post in InsideEd: Higher Ed Cell Cycle Control by Oncogenes and Tumor Suppressors: Driving the
Groups Ask Congress to Delay
Transformation of Normal Cells into Cancerous Cells
"Credit" Rules
By: Am y Y. Chow , Ph.D. (Division of Tumor Cell Biology, Beckman Research Institute, City of Hope) © 2010 Nature Education
New post in Bioscience Citation: Chow , A. Y. (2010) Cell Cycle Control by Oncogenes and Tum or Suppressors: Driving the
eLearning: Write once, publish Transform ation of Norm al Cells into Cancerous Cells. Nature Education 3(9):7
many connecting w ith students
New post in Student Voices: The How is a normal cell transformed into a cancerous cell? The proteins involved in cell division
Tangle of the NatureNurture
Debate events no longer appropriately drive progression from one cell cycle stage to the next.
How is a normal cell transformed into a cancerous cell? The proteins involved in regulating cell division events no longer appropriately drive progression
from one cell cycle stage to the next. Rather than lacking function, cancer cells reproduce at a rate far beyond the normally tightly regulated boundaries
Within this Topic (22)
of the cell cycle. Cancer can be distinguished from many other human diseases because its root cause is not a lack of, or reduction in, cell function. For
Basic (5) example, individuals w ith diabetes may lack insulin production or the ability to respond to insulin. With coronary heart disease, poor blood supply to the
Intermediate (12) heart can cause the organ to eventually fail. In the case of acquired immune deficiency syndrome (AIDS), the immune system loses the cells it needs to
Advanced (5) fend off infection. And w ith many infectious diseases, foreign microorganisms w reak havoc on the host they have invaded, causing a loss of function
w ithin cells, tissues or entire organ systems. Cancers, how ever, occur due to an alteration of a normal biological process — cell division.
Related Topics Cells that progress through the cell cycle unchecked may eventually form malignant tumors, w here masses of cells grow and divide uncontrollably, then
Genetics develop the ability to spread and migrate throughout the body. Fortunately, cancer prevention usually occurs through the strict regulation of the cell cycle
Cell Biology by groups of proteins that interact w ith each other in a very specific sequence of events. It is these events that determine w hether the cell cycle w ill go
Cell Origins and Metabolism forw ard or remain stalled betw een stages.
Proteins and Gene Expression
Subcellular Compartments Given that cancer is fundamentally a disorder at the cellular level, the
Cell Communication technological achievement of cultivating cells in vitro, or outside the organism
Cell Cycle and Cell Division as a w hole, has allow ed investigators to determine w hat events lead to tumor
People Groups Here w e focus on the transformation assay, w hich scientists first used to identify oncogenes and tumor suppressors and study their affect on cell cycle
progression. Even more important w ill be understanding the specific sequence of events in w hich multiple oncogenes and tumor suppressors must act in
combination to promote cancerous cell grow ths (Kinzler 1996; Hahn 2002).
Nature
Education
Early Work in Tumor Biology Led to the Discovery of a Standard Technique: The Transformation Assay
Nick As early as 1911, Peyton Rous demonstrated through his studies of tumorous grow ths in chickens that the potential for tumor generation could be
Morris transferred from animal to animal in cellfree extracts. These extracts w ere eventually show n to contain viruses, w hose ability to promote abnormally
increased cell division in their hosts served to enhance their ow n replication. Thus the same processes stimulated by viral replication could lead to tumor
Ras
production. This field of tumor virology w as instrumental in developing the "cellular transformation assay" still used today to assess tumor grow th.
Kw eku
How do transformed cells grow ? First, they no longer require contact w ith the
Colin
surface of a culture dish. The transformed cells are, instead, capable of
Brow ne
replicating in agar or in suspension (Figure 2). This ability reflects a cancer
Anayansi cell's enhanced mobility, its ability to break dow n substances around it in order
Sierralta to create more space to grow and divide, and a reduction in the contact
inhibition that normally prevents the cells from becoming too crow ded.
Vincent Second, transformed cells w ill grow in more than one layer, producing Figure 2: Transform ation assay for m ouse fibroblasts
Shyu abnormally abundant layers of cells. While untransformed cells grow parallel
in orientation to one another in a single layer, transformed cells w ill pile up in As pictured in (c), transformed cells w ill form a focus (plural: foci),
Deb
chaotic fashion (Figure 1). This feature is reminiscent of cancer cells that or colony, of cells grow ing at a very high density. Here,
Majszak
have reduced contact inhibition of grow th. A third characteristic of transformation occurs in the absence of Kruppellike factor 4
Jennifer transformed cells is their requirement for few er nutrients in the media. This (KLF4), a transcription factor w ith tumor suppressive activity in
Schisa reflects tumor cells' ability to grow and divide even in the absence of grow th colorectal cancer. Normal, nontransformed cells, do not progress
factors. Finally, transformed cells overcome the restriction of limited rounds of past a four cell stage as depicted in panels (a) and (b).
next replication seen in normal cells and essentially become immortal (Varmus © 2009 Nature Publishing Group Hagos, E. G., A. M. Ghaleb, et
1983). al. Mouse em bryonic fibroblasts null for the Krüppel-like
factor 4 gene are genetically unstable. Oncogene 28, 1197-
open in browser customize free license pdfcrowd.com
Blogs factor 4 gene are genetically unstable. Oncogene 28, 1197-
Researchers made use of these results from early virology studies w ith 1205 (2009). All rights reserved.
cellular assays. In these experiments, they infected the cultured cells w ith
Student Voices
various viruses and then looked for "transformations" to occur (Todaro 1966).
Since viral genomes are relatively small, researchers could more easily determine the genetic components responsible for transformation. In fact, the first
Creature Cast
oncogenes they identified w ere derived from viruses and called viral oncogenes. Remarkably, researchers soon also realized that the source of these
NatureEdCast viral oncogenes came from cellular counterparts that had been transferred by viruses from one cell to another (Varmus 1983).
Sim ply Science The Accelerator Gets Stuck: Activated Oncogenes Drive Uncontrolled Cell Cycling
What, then, are oncogene products? These are the proteins involved in cell
cycle regulation that operate by stimulating cellular grow th and division (Figure
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3). A common analogy equates oncogenes to an automobile's gas pedal stuck
in the acceleration mode. Though the driver does not have his foot on the
pedal, the car continues to speed up. Likew ise, oncogenes code for proteins
that function to drive the cell cycle forw ard, typically causing cells to proceed
from one of the G (gap) phases to either chromosome replication (S phase) or
chromosome segregation (mitosis). Examples include receptors at the cell
surface that bind to grow th factors, proteins that interact w ith DNA to initiate
replication, and signaling molecules that link the receptors to the replication
initiators through various pathw ays.
In their normal state, genes that code for the normal proteins controlling these
critical processes are called protooncogenes. How ever, once they are
altered (see below ) to become oncogenes, their abnormal protein products
exhibit increased activity that contributes to tumor grow th. Therefore, instead
of stopping w ithin a G phase as it normally should, a tumor cell continues to
progress through subsequent phases of the cell cycle, leading to uncontrolled Figure 3: Cell cycle control by tum or suppressors and
cell division. In addition, oncogenes can also rescue cells from programmed oncogenes
cell death. Checkpoints are depicted as thick red bars. The stages of the cell
cycle (G1: Gap 1, S: DNA synthesis, G2: Gap 2, and M: mitosis) are
How does a protooncogene become converted to an oncogene? (Figure 4) indicated. Tumor suppressors act to maintain checkpoints (arrow s)
Occasionally, mutations w ill permanently activate proteins that normally w hereas oncogenes allow for checkpoints to be overcome (stop
interchange betw een active or inactive states. For example, Ras proteins lines) (Adapted from Kopnin 2000).
function as molecular sw itches that are turned on and off depending on the
© 2010 Nature Education All rights reserved.
form of nucleotide (diphosphate or triphosphate) to w hich it is bound. In an
"on" state, the products of these protooncogenes relay proliferation
stimulating signals. Problems arise, how ever, w hen mutations convert the protooncogene to an oncogene, rendering Ras permanently active regardless
of the signals the cell receives.
The protooncogene (top) is depicted as a regulatory sequence (RS) follow ed by the coding region (gene). In the first example, a star indicates
the location of the nucleotide substitution on the transcribed portion of the gene. In the case of the translocation example, a different regulatory
sequence becomes responsible for stimulating transcription of a resultant fusion protein. For the amplification example, the presence of multiple
copies of the gene results in excessive expression (Adapted Kufe et al. 2003).
© 2010 Nature Education All rights reserved.
A second type of genetic alteration that converts a protooncogene to an oncogene is a chromosomal translocation. This occurs w hen the pieces of
broken chromosomes reattach haphazardly, leading either to the formation of a fusion protein containing the Nterminus of one protein and the Cterminus
of another, or leading to altered regulation of protein expression (Figure 4). One example of an oncogene generated by this type of chromosomal
translocation is BCR/ABL, w hose protein product consists of the Nterminus of Bcr (breakpoint cluster region) and the Cterminus of Abl, a tyrosine
kinase that relays proliferative signals. The fused chromosome is know n as the Philadelphia chromosome, and it is w idely present in patients w ith chronic
myelogenous leukemia, a blood cell cancer. Formation of the fusion protein renders Abl permanently active, leading to unregulated cell cycling.
Yet another means of generating oncogenes does not change the protooncogene directly at all. Instead, the protooncogene may exist in multiple copies
in the cell, resulting in amplified expression. This is the case for cMYC, for w hich 8 to 30 copies are present in each HL60 cell, a promyelocytic leukemia
cell line. As myc is a transcription factor, its increased expression w ill, in turn, lead to the increased expression of its transcriptional targets, many of
w hich function to drive the cell cycle forw ard. Since all of these genetic alterations result in a gain of function, only one affected chromosome is needed
to induce the transformed cell phenotype (Vogelstein 2002).
One of the beststudied factors of this type is a protein know n as retinoblastoma protein (pRb) and its corresponding gene, RB1, the first tumor
suppressor gene to be identified. Since pRb activity stops the expression of genes required for progression into S phase of the cell cycle, its inactivation
allow s for uncontrolled cell division (Figure 3). In fact, this principle applies to all tumor suppressors: genetic alterations in the gene leading to
tumorigenesis prevent the regulatory protein from inhibiting cell proliferation. In other w ords, w hen the brakes on a car don't w ork, the car cannot stop.
The types of genetic alterations leading to pRb inactivity most often involve frameshifts or deletions in the RB1 gene causing premature introduction of a
stop codon and defective protein expression. In some instances, expression of pRb may be normal, but the pathw ay in w hich it functions is defective
due to inactivity of other pathw ay components. By definition, then, these other components w ould also be considered tumor suppressors (Burkhart,
2008).
Yet another example of a tumor suppressor, and the most commonly mutated gene in human tumors, is the p53 gene (Vogelstein, 2004). As a
transcription factor that activates expression of proliferationinhibiting and apoptosispromoting proteins in response to DNA damage, p53 plays a critical
role in maintaining the G1 to S cell cycle checkpoint (Figure 3). Genetic alterations that inactivate p53 w ill inhibit the DNA damage response that prevents
cell cycle progression. When this occurs, a cell continues to divide even in the presence of DNA damage. Since inactivation of tumor suppressors results
in a loss of function, both maternal and paternal copies of a gene coding for a tumor suppressor must usually be altered for tumorigenesis to occur —
one good copy of the gene may provide sufficient activity for the cell to maintain proper grow th and division.
In contrast to the first oncogenes that w ere identified through investigations in tumor virology, the first tumor suppressors (e.g., retinoblastoma geneRB)
w ere described follow ing analysis of pedigrees of children afflicted w ith familial retinal tumors. In line w ith the idea that multiple genetic alterations are
often necessary for fullblow n tumor progression, these individuals also exhibited defects in other pathw ays affecting cell grow th and division. And
although it has since been established that having tw o defective copies of RB is the most critical feature that initiates tumor development in many
different types of cancer, the fact that other genetic events must occur highlights the need for further understanding the tumorigenesis process
(Burkhart 2008).
With the fully sequenced human genome and a multitude of strategies for genetic analysis of individuals (e.g., single nucleotide polymorphism analysis,
microarray analysis, linkage analysis, sequencing individual genomes), discovery of new genes influencing tumor initiation continues at a rapid pace.
Delineating the pathw ays affected by these genes, and the role they play in controlling the cell cycle, may prove more challenging (Vogelstein 2004).
The cellular transformation assay described above w as a start, but scientists must also demonstrate that particular genetic alterations are both
Summary
Tw o classes of genes, oncogenes and tumor suppressor genes, link cell cycle control to tumor formation and development. Oncogenes in their proto
oncogene state drive the cell cycle forw ard, allow ing cells to proceed from one cell cycle stage to the next. This highly regulated process becomes
dysregulated due to activating genetic alterations that lead to cellular transformation. Tumor suppressor genes, on the other hand, restrict cell cycle
progression. Their control over cell division is lost w ith genetic alterations leading to their inactivation. The role that both types of genes play in tumor
formation can be experimentally determined using in vitro transformation assays or more complex in vivo animal models. These sorts of experiments w ill
lead to a more thorough understanding of the genetic basis for cancer, more effective therapeutics, and a deeper appreciation of the intricacies of cell
cycle regulation.
Burkhart, D. L. & Sage, J. Cellular mechanisms of tumour suppression by the retinoblastoma gene. Nature Reviews Cancer 8, 671–682 (2008).
Hahn, W. C. & Weinberg, R. A. Rules for making human tumor cells. New England Journal of Medicine 347, 1593–1603.
Kinzler, K. W. & Vogelstein, B. Lessons from hereditary colorectal cancer. Cell 87, 159–170 (1996).
Kopnin, B. P.Targets of oncogenes and tumor suppressors: key for understanding basic mechanisms of carcinogenesis. Biokhimiya 65, 2–27 (2000).
Kufe, D. W., Pollock, R. E., et al. eds. HollandFrei Cancer Medicine. Hamilton, Ontario: BC Decker, 2003.
Sung, Y.M., Xu, X., et al. Tumor suppressor function of syk in human MCF10A in vitro and normal mouse mammary epithelium in vivo. PLoS ONE 4,
e7445.
Todaro, G. J. & Green, H. High frequency of SV40 transformation of mouse cell line 3T3. Virology 28, 756–759 (1966).
Varmus, H. & Levine, A. J. eds. Readings in Tumor Virology. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory, 1983.
Vogelstein, B. & Kinzler, K. W. Cancer genes and the pathw ays they control. Nature Medicine 10, 789–799 (2004).
Vogelstein, B. & Kinzler, K. W. The Genetic Basis of Human Cancer. 2nd ed. New York, NY: McGraw Hill Medical Publishing Division, 2002.
Yu, C. I., Gallegos, M., et al. Broad influenzaspecific CD8+ Tcell responses in humanized mice vaccinated w ith influenza virus vaccines. Blood 112,
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