UI - 11341983
AU - Cho J; Baek W; Yang S; Chang J; Sung YC; Suh M
HCV core protein modulates Rb pathway through pRb down-regulation and
SO - Biochim Biophys Acta 2001 Feb 5;1538(1):59-66
AD - Department of Microbiology, College of Medicine, Seonam University,
Namwon, South Korea.
It has been recognized that the HCV (hepatitis C virus) core protein
plays an important role in hepatocarcinogenesis. The functional
inactivation of the Rb pathway appears to be a major event for
multi-step cancer carcinogenesis. To elucidate the role of the HCV core
protein in hepatocarcinogenesis, we investigated the effect of the HCV
core protein on the Rb pathway in both Rat-1 cell lines, stably
expressing the HCV core protein and the doxycycline-regulated cell
lines. The HCV core stable transfectants showed a dramatic decrease in
the pRb levels and E2F-1 up-regulation. In the doxycycline-regulated
cell lines, the pRb levels were significantly decreased which are
followed by E2F-1 up-regulation. HCV core stable transfectants showed
higher cell growth rates and were sensitize to apoptosis. Thus, our
results first indicate that the HCV core protein decreases the
expression of pRb, thereby allowing E2F-1 to be constitutively active,
which is thought to result in rapid cell proliferation or sensitizing to
UI - 10908559
AU - Nickoloff BJ; Chaturvedi V; Bacon P; Qin JZ; Denning MF; Diaz MO
Id-1 delays senescence but does not immortalize keratinocytes.
SO - J Biol Chem 2000 Sep 8;275(36):27501-4
AD - Department of Pathology and the Department of Medicine, Loyola
University Medical Center, Maywood, Illinois 60153, USA.
Defining the molecular basis responsible for regulating the
proliferative potential of keratinocytes has important implications for
normal homeostasis and neoplasia of the skin. Under current culture
conditions, neonatal foreskin-derived human keratinocytes possess a
relatively short replicative lifespan. Recently it was reported that
forced overexpression of the helix-loop-helix protein Id-1 was capable
of immortalizing keratinocytes, secondary to activation of telomerase
activity and suppression of p16/Rb-mediated growth arrest pathways. To
investigate the relationship between Id-1, telomerase activity, telomere
length, p16, Rb cell cycle regulators, and senescence, whole populations
of keratinocytes were infected with a retrovirus to induce
overexpression of Id-1. In these unselected cultures, enhanced Id-1
levels clearly extended the lifespan of keratinocytes, but Id-1 did not
prevent the onset of replicative senescence. Under these experimental
conditions, Id-1 expression did not trigger induction of telomerase
activity, and there was progressive shortening of the telomeres that was
accompanied by elevated p16 levels and prevalence of active Rb. The
ability of Id-1 to postpone, but not prevent, senescence may be related
to partial inhibition of p16 expression, as the Id-1-overexpressing
cultures displayed a decreased capacity for
12-O-tetradecanoylphorbol-13-acetate-mediated p16 induction. Thus, while
no immortalization was observed, Id-1 could delay the onset of
replicative senescence in unselected human keratinocyte populations.
UI - 11840325
AU - Lasorella A; Uo T; Iavarone A
Id proteins at the cross-road of development and cancer.
SO - Oncogene 2001 Dec 20;20(58):8326-33
AD - Department of Neurology, Developmental and Molecular Biology, Albert
Einstein College of Medicine, Bronx, NY 10461, USA.
A large body of evidence has been accumulated that demonstrates dominant
effects of Id proteins on different aspects of cellular growth.
Generally, constitutive expression of Id not only blocks cell
differentiation but also drives proliferation. In some settings, it is
sufficient to render cells immortal or induce oncogenic transformation.
The participation of Id proteins in advanced human malignancy, where
they are frequently deregulated, has been dramatically bolstered by the
recent discovery that Id exert pivotal contributions to many of the
essential alterations that collectively dictate malignant growth.
Relentless proliferation associated with self-sufficiency in growth
signals and insensitivity to growth inhibitory signals, sustained
neoangiogenesis, tissue invasiveness and migration capabilities of tumor
cells all share dependency on the unlimited availability of Id proteins.
It is remarkable that many of these features recapitulate those
physiologically propelled by Id proteins to support normal development.
We propose that the participation of Id in multiple fundamental traits
of cancer may be the basis for unprecedented therapeutic opportunities.
UI - 8381218
AU - Caruso M; Martelli F; Giordano A; Felsani A
Regulation of MyoD gene transcription and protein function by the
transforming domains of the adenovirus E1A oncoprotein.
SO - Oncogene 1993 Feb;8(2):267-78
AD - Istituto Biologia Cellulare, CNR, Rome, Italy.
It has been demonstrated that the adenovirus E1A gene products inhibit
myogenic differentiation in the mouse C2 muscle cell line. During
myogenic differentiation, cell growth and tissue-specific gene
expression are mutually exclusive. Since E1A exerts multiple effects on
different cellular pathways through alteration of cell growth control
and transcriptional regulation, we investigated in more detail the
molecular mechanisms underlying the inhibitory effect of E1A on myogenic
differentiation. To this end, we used mutant derivatives of E1A that
lack the 'conserved domain' sequences to which the functional domains of
E1A have been mapped, and we observed the effect of constitutive
expression of these E1A mutants on myogenesis in the murine C2 muscle
cell line. Our results demonstrate that E1A interferes with myogenesis
through at least two mechanisms: (i) the inhibition of MyoD expression;
(ii) the repression of MyoD-dependent transcriptional activation. In
addition, we demonstrate also that the repression of MyoD transcription
depends upon sequences located in the N-terminus of E1A and correlates
well with the site of E1A/p300 association. Further, the inhibition of
transcriptional activation by MyoD depends both on conserved region 1
and on conserved region 2, the two transforming domains of E1A. We
demonstrate also that a similar inhibitory effect on the MyoD
transactivating function is provided by the polyomavirus and SV40 large
UI - 7937596
AU - Roncalli M; Bulfamante G; Viale G; Springall DR; Alfano R; Comi A;
Maggioni M; Polak JM; Coggi G
C-myc and tumour suppressor gene product expression in developing and
term human trophoblast.
SO - Placenta 1994 Jun;15(4):399-409
AD - II Department of Pathology, University of Milan, School of Medicine,
Proliferation and differentiation of villous trophoblast during
placental development, from an early stage to full-term, were
investigated in routinely fixed and processed tissues, by means of the
immunocytochemical localization of the cell cycle-related proto-oncogene
c-myc and the p53 and retinoblastoma susceptibility (Rb)
tumour-suppressor gene products. The proliferative activity of the
trophoblast was determined using an antibody against proliferating cell
nuclear antigen (PCNA) which stains all proliferating cells in
paraffin-embedded tissues. Diffuse nuclear immunoreactivity for PCNA,
c-myc and Rb gene products was a consistent finding in early
cytotrophoblast; c-myc product expression was also detectable in both
layers of mid-gestation trophoblast. Only scattered cytotrophoblastic
nuclei of early gestational placenta displayed immunostaining for p53
gene product. In full-term placenta c-myc expression was undetectable
while Rb gene product and PCNA immunoreactivity declined markedly. These
results indicate that the expression of the above genes is
spatio-temporally regulated during placental development. A potential
involvement of the oncosuppressor gene products p53 and Rb in the
control of trophoblastic proliferation and of c-myc in the control of
both the proliferative and differentiation pathways of trophoblastic
cells is suggested.
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