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Current Molecular Medicine
ISSN: 1566-5240
Current Molecular Medicine
Volume 6, Number 7, November 2006
Contents
Editorial Pp. 703-704
The Retinoblastoma Tumour Suppressor in Model Organisms–New
Insights from Flies and Worms Pp. 705-711
Michael Korenjak and Alexander Brehm
[Abstract]
Rb at the Interface Between Cell Cycle and Apoptotic
Decisions Pp. 713-718
Rachel B. Delston and J. William Harbour
[Abstract]
Rb Function in the Apoptosis and Senescence of Non-Neuronal
and Neuronal Cells: Role in Oncogenesis Pp. 719-729
Piyali Dasgupta, Jaya Padmanabhan and Srikumar Chellappan
[Abstract]
Putting the Oncogenic and Tumor Suppressive Activities
of E2F into Context Pp. 731-738
David G. Johnson and James DeGregori
[Abstract]
Distinct and Overlapping Roles for E2F Family Members
in Transcription, Proliferation and Apoptosis Pp.
739-748
James DeGregori and David G. Johnson
[Abstract]
Role of the Retinoblastoma Tumor Suppressor in the
Maintenance of Genome Integrity Pp. 749-757
Erik S. Knudsen, Charlene R. Sexton and Christopher N.
Mayhew
[Abstract]
Insights from Animal Models on the Origins and Progression
of Retinoblastoma Pp. 759-781
Marek Pacal and Rod Bremner
[Abstract]
Retinoblastoma Regulatory Pathway in Lung Cancer
Pp. 783-793
Kathryn A. Wikenheiser-Brokamp
[Abstract]
Cervical Cancer and Human Papillomaviruses: Inactivation
of Retinoblastoma and Other Tumor Suppressor Pathways
Pp. 795-808
Elizabeth E. Jones and Susanne I. Wells
[Abstract]
The Retinoblastoma Protein in Osteoblast Differentiation
and Osteosarcoma Pp. 809-817
Amit Deshpande and Philip W. Hinds
[Abstract]
Abstracts
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Editorial
OVERVIEW
The concept that the retinoblastoma arises as a result
of two discrete genetic hits in the same tumor suppressor
gene has been in existence for greater than 20 years [1-4].
Cloning and analyses of the retinoblastoma tumor suppressor
gene (Rb) revealed that this same tumor suppressor is mutated
not only in retinoblastoma, but in a litany of other tumor
types (e.g. bladder cancer, osteosarcoma, lung cancer and
breast cancer) [5-9]. Subsequent studies demonstrated that
in many additional tumors, the RB protein can be inactivated
by a multitude of mechanisms [10-12]. For example, the E7
protein of human papilloma virus directly binds and inactivates
the RB protein in cervical cancer [13, 14]. Additionally,
RB is functionally inactivated by deregulated phosphorylation
in those tumors which lack the p16ink4a tumor suppressor or
harbor excessive CDK4 and cyclin D1 oncogenes [10, 12, 15].
The frequency of functional disruption of the retinoblastoma
tumor suppressor in human cancers has precipitated significant
efforts to define its modes of action. In general, these studies
have been focused on two areas:
1. Defining Physiological/Biochemical Function
Analyses of RB function in vitro or in cell culture
models have defined the mechanisms through which RB is regulated
and those biological processes which are governed by RB. RB
action encompasses control of cell cycle, regulation of apoptosis,
control of genomic stability, and modulation of differentiation
[10, 16-19]. Each process is known to be altered in human
cancer, and the influence of RB on each pathway is reviewed
in this issue.
2. Delineating Tissue Specific Actions in Tumor Suppression
RB and critical interacting factors are conserved in metazoans.
As a result, it has been possible to study the functionality
of RB in multiple organisms [20-23]. These models have been
used to uncover the consequence of RB loss related to organismal
development and tumorigenesis, and have revealed that RB likely
utilizes distinct mechanisms to suppress tumorigenesis in
specific tissues. Corresponding reviews discuss the disparate
functions of RB in discrete model organisms, context dependent
RB action and implications for tumor suppression.
Taken together the body of work described in this issue and
additional research, which regrettably due to space constraints
could not be included herein, have provided significant insights
into the action of RB in cancer.
CHALLENGE FOR THE FUTURE
Cloning of the Rb tumor suppressor, provided great promise
that knowledge of such inhibitors of oncogenic proliferation
would represent ideal nodes for the treatment of cancer.
The concept that molecules like RB could be used to treat
cancer was originally supported by studies demonstrating that
reintroduction of functional RB protein into retinoblastoma
cell lines could inhibit tumorigenic proliferation [24]. Indeed,
today we can readily inhibit the proliferation of virtually
any tumor cell type via manipulation of RB function [25-27].
While it is well appreciated that restoring the activity of
a factor, such as RB, lost in cancer can be quite difficult,
there are now clear instances where restoration of tumor suppressive
signaling pathways can be achieved through pharmacological
means. This is perhaps best demonstrated in the context of
the p53 tumor suppressor [28-30], wherein multiple therapeutic
agents have been shown to unleash the nascent p53 activity
present in many tumor cells. Such approaches can be similarly
applied to the RB pathway, wherein in many instances RB inactivation
is achieved not through mutation but through other mechanisms.
Unfortunately, RB has apparently failed to receive the level
of exploration directed against p53 and other tumor suppressive
pathways.
Since RB loss occurs in many cancers and modifies the response
to a variety of therapeutic agents [31-33], RB status could
provide a critical diagnostic/prognostic basis upon with to
direct treatment. While this concept is not new and a plethora
of studies have evaluated RB status in disease outcome and
therapeutic response, testing for RB status is largely confined
to retinoblastoma susceptibility and is not yet used as the
basis to direct therapy [34-37].
In summary, identification and study of the RB tumor suppressor
has provided an essential knowledge basis for delineating
endogenous mechanisms that protect against tumor formation.
Significant advances in our understanding of RB funtion have
unexpectedly revealed that its tumor suppressive activity
extends to many 704 Current Molecular Medicine, 2006, Vol.
6, No. 7 Editorial disparate cellular pathways and that RB
function is often tissue specific. Current challenges remain
on how to harness this information and apply this detailed
understanding of RB action to the improvement of cancer diagnosis
and therapy.
REFERENCES
[1] Cavenee, W.K., Dryja, T.P., Phillips, R.A., Benedict,
W.F., Godbout, R., Gallie, B.L., Murphree, A.L., Strong, L.C.
and White, R.L. (1983) Nature, 305,
779-84.
[2] Cavenee, W.K., Hansen, M.F., Nordenskjold, M., Kock, E.,
Maumenee, I., Squire, J.A., Phillips, R.A. and Gallie, B.L.
(1985) Science, 228, 501-3.
[3] Dryja, T.P., Cavenee, W., White, R., Rapaport, J.M., Petersen,
R., Albert, D.M. and Bruns, G.A. (1984) N. Engl. J. Med.,
310, 550-3.
[4] Knudson, A.G., Jr. (1971) Proc. Natl. Acad. Sci. USA,
68, 820-3.
[5] Hansen, M.F., Koufos, A., Gallie, B.L., Phillips, R.A.,
Fodstad, O., Brogger, A., Gedde-Dahl, T. and Cavenee, W.K.
(1985) Proc. Natl. Acad. Sci. USA, 82,
6216-20.
[6] Lee, W.H., Bookstein, R., Hong, F., Young, L.J., Shew,
J.Y. and Lee, E.Y. (1987) Science, 235,
1394-9.
[7] Friend, S.H., Bernards, R., Rogelj, S., Weinberg, R.A.,
Rapaport, J.M., Albert, D.M. and Dryja, T.P. (1986) Nature,
323, 643-6.
[8] Horowitz, J.M., Park, S.H., Bogenmann, E., Cheng, J.C.,
Yandell, D.W., Kaye, F.J., Minna, J.D., Dryja, T.P. and Weinberg,
R.A. (1990) Proc. Natl. Acad. Sci. U S A, 87,
2775-9.
[9] Harbour, J.W., Lai, S.L., Whang-Peng, J., Gazdar, A.F.,
Minna, J.D. and Kaye, F.J. (1988) Science, 241,
353-7.
[10] Cobrinik, D. (2005) Oncogene, 24,
2796-809.
[11] Wang, J.Y., Knudsen, E.S. and Welch, P.J. (1994) Adv.
Cancer Res., 64, 25-85.
[12] Mittnacht, S. (1998) Curr. Opin. Genet. Dev.,
8, 21-7.
[13] Dyson, N., Howley, P.M., Munger, K. and Harlow, E. (1989)
Science, 243, 934-7.
[14] Munger, K., Werness, B.A., Dyson, N., Phelps, W.C., Harlow,
E. and Howley, P.M. (1989) EMBO J., 8,
4099-105.
[15] Sherr, C.J., Kato, J., Quelle, D.E., Matsuoka, M. and
Roussel, M.F. (1994) Cold Spring Harb. Symp. Quant. Biol.,
59, 11-9.
[16] Thomas, D.M., Yang, H.S., Alexander, K. and Hinds, P.W.
(2003) Cancer Biol. Ther., 2, 124-30.
[17] Chau, B.N. and Wang, J.Y. (2003) Nat. Rev. Cancer,
3, 130 8.
[18] Zheng, L. and Lee, W.H. (2002) Adv. Cancer Res.,
85, 13-50.
[19] Dimova, D.K. and Dyson, N.J. (2005) Oncogene,
24, 2810-26.
[20] Du, W., Vidal, M., Xie, J.E. and Dyson, N. (1996) Genes
Dev., 10, 1206-18.
[21] Lu, X. and Horvitz, H.R. (1998) Cell, 95,
981-91.
[22] Jacks, T., Fazeli, A., Schmitt, E.M., Bronson, R.T.,
Goodell, M.A. and Weinberg, R.A. (1992) Nature, 359,
295-300.
[23] Lee, E.Y., Chang, C.Y., Hu, N., Wang, Y.C., Lai, C.C.,
Herrup, K., Lee, W.H. and Bradley, A. (1992) Nature,
359, 288-94.
[24] Huang, H.J., Yee, J.K., Shew, J.Y., Chen, P.L., Bookstein,
R., Friedmann, T., Lee, E.Y. and Lee, W.H. (1988) Science,
242, 1563-6.
[25] Knudsen, K.E., Weber, E., Arden, K.C., Cavenee, W.K.,
Feramisco, J.R. and Knudsen, E.S. (1999) Oncogene,
18, 5239 45.
[26] Xu, H.J., Zhou, Y., Seigne, J., Perng, G.S., Mixon, M.,
Zhang, C., Li, J., Benedict, W.F. and Hu, S.X. (1996) Cancer
Res., 56, 2245-9.
[27] Lukas, J., Herzinger, T., Hansen, K., Moroni, M.C., Resnitzky,
D., Helin, K., Reed, S.I. and Bartek, J. (1997) Genes
Dev., 11, 1479-92.
[28] Bouchet, B.P., de Fromentel, C.C., Puisieux, A. and Galmarini,
C.M. (2006) Crit. Rev. Oncol. Hematol., 58,
190-207.
[29] Vassilev, L.T., Vu, B.T., Graves, B., Carvajal, D., Podlaski,
F., Filipovic, Z., Kong, N., Kammlott, U., Lukacs, C., Klein,
C., Fotouhi, N. and Liu, E.A. (2004) Science, 303,
844-8.
[30] Bykov, V.J., Issaeva, N., Shilov, A., Hultcrantz, M.,
Pugacheva, E., Chumakov, P., Bergman, J., Wiman, K.G. and
Selivanova, G. (2002) Nat. Med., 8,
282-8.
[31] Harrington, E.A., Bruce, J.L., Harlow, E. and Dyson,
N. (1998) Proc. Natl. Acad. Sci. USA, 95,
11945-50.
[32] Almasan, A., Yin, Y., Kelly, R.E., Lee, E.Y., Bradley,
A., Li, W., Bertino, J.R. and Wahl, G.M. (1995) Proc.
Natl. Acad. Sci. USA, 92, 5436-40.
[33] Mayhew, C.N., Perkin, L.M., Zhang, X., Sage, J., Jacks,
T. and Knudsen, E.S. (2004) Oncogene, 23,
4107-20.
[34] Goddard, A.D., Phillips, R.A., Greger, V., Passarge,
E., Hopping, W., Zhu, X.P., Gallie, B.L. and Horsthemke, B.
(1990) Clin. Genet., 37, 117-26.
[35] Sugano, K., Yoshida, T., Izumi, H., Umezawa, S., Ushiama,
M., Ichikawa, A., Hidaka, A., Murakami, Y., Kodama, T., Suzuki,
S. and Kaneko, A. (2004) Int. J. Clin. Oncol., 9,
25-30.
[36] Cohen, J.G., Dryja, T.P., Davis, K.B., Diller, L.R. and
Li, F.P. (2001) Med. Pediatr. Oncol., 37,
372-8.
[37] Smith, B.J. and O'Brien, J.M. (1996) J. Pediatr.
Ophthalmol. Strabismus., 33, 120-3.
Erik S. Knudsen
Department of Cell Biology
University of Cincinnati
Vontz Center for Molecular Studies
3125 Eden Avenue, Cincinnati
OH 45267-0521
USA
Tel: 513-558-8885
Fax: 513-558-4454
E-mail: erik.knudsen@uc.edu
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The Retinoblastoma Tumour Suppressor in Model
Organisms–New Insights from Flies and Worms
Michael Korenjak and Alexander Brehm
All forms of life on Earth share a common ancestry. As
a consequence, Homo sapiens shares a large number
of genes essential for the development and maintenance of
multicellular life with "simple" animals, such as
the fruit fly Drosophila melanogaster and the nematode
worm Caenorhabdites elegans. Indeed, Drosophila
and C. elegans have successfully been used to unravel
fundamental mechanisms underlying animal development. The
sequencing of their genomes has revealed that a surprisingly
large proportion of genes relevant for human disease have
counterparts in the worm and in the fly. This includes many
oncogenes and tumour suppressor genes and provides us with
a unique opportunity to exploit the advantages of simple model
organisms to further our understanding of the molecular basis
of cancer. Recent work on the fly and worm homologs of the
Retinoblastoma tumour suppressor (pRb) has uncovered some
unexpected pRb functions: Evolutionary conserved pRb complexes
participate in cell fate determination, repress germline-specific
gene expression and interact with RNA interference pathways.
Similar complexes appear to operate in human cells.
[Back to top]
Rb at the Interface Between Cell Cycle and Apoptotic
Decisions
Rachel B. Delston and J. William Harbour
The retinoblastoma (RB) gene was the first tumor suppressor
to be identified, and it continues to be the subject of intense
scientific interest. Not only is the RB gene mutated in the
rare eye tumor and some other cancers, the Rb protein is functionally
inactivated in virtually all human cancers, suggesting that
it plays a general role in cellular homeostasis. Rb initially
was envisaged as a simple ‘on-off’ regulator of
the cell cycle, and this function was thought to account for
its role as a tumor suppressor. Subsequently, however, closer
scrutiny revealed unexpected and complex properties of Rb
that together contribute to the unique role of Rb in cell
biology. For example, Rb appears to be dispensable for normal
cell cycling, but it has a special role in triggering permanent
cell cycle exit associated with differentiation and senescence.
Further, although the role of Rb as tumor suppressor is firmly
established, it also has the ability to block apoptosis, which
is generally thought to be a property of oncogenes. Our lab
has been interested in understanding the dual and seemingly
incongruous roles of Rb in cell cycle control and apoptosis.
For many of these studies, we have chosen the melanocyte lineage
as a model cell system because of the established role for
Rb in melanocyte differentiation and survival, and the frequent
deregulation of the Rb pathway in melanoma.
[Back to top]
Rb Function in the Apoptosis and Senescence
of Non-Neuronal and Neuronal Cells: Role in Oncogenesis
Piyali Dasgupta, Jaya Padmanabhan and Srikumar Chellappan
Regulators of the cell cycle machinery play a major role
in modulating a variety of cellular phenomena including proliferation,
quiescence, differentiation, senescence and apoptosis. Studies
in the past decade have clearly established a role for the
retinoblastoma tumor suppressor protein, Rb, and its primary
downstream target E2F1, in the above processes. While the
role of the Rb protein in the regulation of cell cycle progression
has been analyzed in great detail, its potential roles in
apoptosis as well as senescence are relatively less studied.
It has become increasingly clear that the anti-apoptotic functions
of Rb contribute significantly to the genesis and progression
of tumors. This is especially relevant in neuronal systems,
since terminally differentiated neurons do not proliferate;
therefore the normal anti-proliferative functions of Rb in
neurons are not very dominant. This chapter describes the
current thoughts on the role of Rb function in the apoptosis
and senescence of cells, both of neuronal and non-neuronal
origin. Recent studies have also addressed how Rb function
is differentially modulated by proliferative and apoptotic
signals received at the cell surface, though both lead to
Rb inactivation. The contribution of Rb to inducing cellular
senescence has been long recognized, but the underlying molecular
mechanisms are being elucidated only recently; the contribution
of this function of Rb to tumor suppression remains to be
understood in detail. It can be expected that an understanding
of Rb function in cellular apoptosis and senescence will enhance
our ability to develop novel agents and strategies to combat
cancer.
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Putting the Oncogenic and Tumor Suppressive Activities
of E2F into Context
David G. Johnson and James DeGregori
Deregulation of E2F transcriptional activity as a result
of alterations in the p16INK4a-cyclin D1-Rb pathway
is a hallmark of human cancer. E2F is a family of related
factors that controls the expression of genes important for
cell cycle progression as well as other processes such as
apoptosis, DNA repair, and differentiation. Some E2F family
members are associated with the activation of transcription
and the promotion of proliferation while others are implicated
in repressing transcription and inhibiting cell growth. It
is now becoming clear however, that this view of the E2F family
is overly simplistic and that the role of a given E2F in regulating
transcription and cell growth is highly dependent on context.
This complexity is also evident when analyzing how perturbations
in E2F modulate tumor development. As expected, some E2F family
members are found to be critical for mediating the oncogenic
effects of Rb loss. On the other hand, several E2Fs have tumor
suppressive properties in mouse models and this appears to
be reflected in some human cancers with decreased E2F expression.
Surprisingly, tumor suppressive activity is not associated
with the repressor E2Fs but instead is associated with the
same E2Fs shown to have oncogenic activities. For example,
deregulated E2F1 expression can either promote or inhibit
tumorigenesis depending on the nature of the other oncogenic
mutations that are present. Thus, the ability of some E2F
family members to behave as both oncogene and tumor suppressor
gene can be reconciled by putting E2F into context.
[Back to top]
Distinct and Overlapping Roles for E2F Family
Members in Transcription, Proliferation and Apoptosis
James DeGregori and David G. Johnson
Since the discovery almost fifteen years ago that E2F
transcription factors are key targets of the retinoblastoma
protein (RB), studies of the E2F family have uncovered critical
roles in the control of transcription, cell cycle and apoptosis.
E2F proteins are encoded by at least eight genes, E2F1 through
E2F8. While specific roles for individual E2Fs in mediating
the effects of RB loss are emerging, it is also becoming clear
that there are no simple divisions of labor among the E2F
family. Instead, an individual E2F can function to activate
or repress transcription, promote or impede cell cycle progression
and enhance or inhibit cell death, dependent on the cellular
context. While functional redundancy among E2Fs and the striking
influences of cellular context on the effects of E2F loss
or gain of function have prevented a simple delineation of
unique functions within the E2F family, these complexities
undoubtedly reflect the extensive regulation and importance
of this transcription factor family.
[Back to top]
Role of the Retinoblastoma Tumor Suppressor in
the Maintenance of Genome Integrity
Erik S. Knudsen, Charlene R. Sexton and Christopher
N. Mayhew
The retinoblastoma tumor suppressor (RB) is functionally
inactivated at high frequency in human cancers. Based on the
role of RB as a negative regulator of cell cycle this event
would be expected to contribute to deregulated proliferation.
However, evidence suggests that loss of RB not only mediates
aberrant proliferation, but compromises the fidelity of cell
cycle transitions leading to a breakdown in genome integrity.
This review is focused on the mechanisms underlying this facet
of RB function and the contibution of this process to tumorigenesis.
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Insights from Animal Models on the Origins and
Progression of Retinoblastoma
Marek Pacal and Rod Bremner
The RB gene was discovered 20 years ago because
of its role in the childhood eye cancer retinoblastoma. However,
surprisingly little progress was made in defining the role
of RB protein in the retina. In the last two years, new models
exploiting conditional deletion of the mouse Rb gene
have altered this picture radically. These models provide
insight into the first Rb function, the cell of origin of
retinoblastoma, the window during which Rb acts, distinct
cell-specific defenses against Rb loss, the number
and type of post-Rb lesions required for transformation,
why pediatric tumors exist, the controversial role of the
p53 pathway in retinoblastoma, and the reason why the disease
is virtually unique to humans. Two years have dramatically
improved our understanding of Rb function in the tissue that
gave us this important tumor suppressor.
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Retinoblastoma Regulatory Pathway in Lung Cancer
Kathryn A. Wikenheiser-Brokamp
Lung cancer is the leading cause of cancer related deaths
accounting for more deaths than breast, colon and prostate
cancers combined. The Rb-p16 regulatory pathway plays an essential
role in tumor suppression in the lung epithelium. This is
evidenced by the nearly universal alterations in Rbp16 pathway
components in lung cancer, and the increased incidence of
pulmonary carcinomas in persons with germline Rb mutations.
Interestingly, p16 loss and Rb mutations preferentially occur
in phenotypically distinct lung cancer subtypes. Analysis
of human tumors has identified progressive preneoplastic lesions
that accumulate molecular alterations in an orderly sequence.
Epigenetic p16 gene modifications represent an early event
in lung cancer progression. This review summarizes the human
studies that demonstrate a critical role for the Rb-p16 tumor
suppressor pathway in lung carcinogenesis, and discusses how
these findings in combination with genetically engineered
mouse models have significantly contributed to our understanding
of lung cancer pathogenesis.
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Cervical Cancer and Human Papillomaviruses: Inactivation
of Retinoblastoma and Other Tumor Suppressor Pathways
Elizabeth E. Jones and Susanne I. Wells
Infection with human papillomaviruses (HPVs) is a major
public health burden worldwide and is associated with benign
and malignant lesions of the skin and genital tract. HPV causes
cervical cancer, which represents the second most prevalent
cancer in women worldwide. Functions of the viral oncogenes
E6 and E7 are essential for carcinogenesis and for support
of the viral life cycle. We will begin by discussing the relationship
between HPV infection and disease, followed by a review of
E6 and E7 activities and their respective cellular targets.
Particular emphasis will be placed on established and newly
discovered mechanisms by which E7 inhibits members of the
cellular retinoblastoma protein family. We will then describe
how current research links the above molecular interactions
to malignant transformation as well as to aspects of the viral
life cycle in vitro and in vivo. As a result
of decades of intense HPV research, promising therapies to
prevent infection and to treat HPV associated cancers are
now on the horizon. We will conclude our review by a description
of potential gene therapeutic and hormonal approaches and
of new developments in the design of effective vaccines.
[Back to top]
The Retinoblastoma Protein in Osteoblast Differentiation
and Osteosarcoma
Amit Deshpande and Philip W. Hinds
Osteogenic sarcoma (osteosarcoma) is the most common
primary tumor of bone. It accounts for approximately 19% of
all malignant tumors of the bone. Of all the molecular targets
altered during the genesis of osteosarcoma, the retinoblastoma
gene (RB1) shows the highest frequency of inactivation.
Published data from human osteosarcoma tumors and in vivo
and in vitro model systems support a role for the
retinoblastoma gene family in bone development and tumorigenesis.
Although a variety of bone tumors, depending on the cell of
origin, including osteoclasts or osteoclast-like cells, chondroblasts,
and fibroblasts, are described, for the purpose of this review
we will focus primarily on the tumors arising from the osteoblast
lineage.
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