UI - 21431978
AU - Thomas DM; Carty SA; Piscopo DM; Lee JS; Wang WF; Forrester WC; Hinds PW
The retinoblastoma protein acts as a transcriptional coactivator
required for osteogenic differentiation.
SO - Mol Cell 2001 Aug;8(2):303-16
AD - Department of Pathology and, Harvard Medical School, 200 Longwood
Avenue, Boston, MA 02115, USA.
The incidence of osteosarcoma is increased 500-fold in patients who
inherit mutations in the RB gene. To understand why the retinoblastoma
protein (pRb) is specifically targeted in osteosarcoma, we studied its
function in osteogenesis. Loss of pRb but not p107 or p130 blocks late
osteoblast differentiation. pRb physically interacts with the osteoblast
transcription factor, CBFA1, and associates with osteoblast-specific
promoters in vivo in a CBFA1-dependent fashion. Association of pRb with
CBFA1 and promoter sequences results in synergistic transactivation of
an osteoblast-specific reporter. This transactivation function is lost
in tumor-derived pRb mutants, underscoring a potential role in tumor
suppression. Thus, pRb functions as a direct transcriptional coactivator
promoting osteoblast differentiation, which may contribute to the
targeting of pRb in osteosarcoma.
UI - 21435046
AU - Kleihues P; Ohgaki H
Primary and secondary glioblastomas: from concept to clinical diagnosis.
SO - Neuro-oncol 1999 Jan;1(1):44-51
AD - International Agency for Research on Cancer (IARC), World Health
Organization (WHO), Lyon, France.
Glioblastomas may develop de novo (primary glioblastomas) or through
progression from low-grade or anaplastic astrocytomas, (secondary
glioblastomas). These subtypes of glioblastoma constitute distinct
disease entities that evolve through different genetic pathways, affect
patients at different ages, and are likely to differ in prognosis and
response to therapy. Primary glioblastomas develop in older patients and
typically show EGFR overexpression, PTEN (MMAC1) mutations, CDKN2A (p16)
deletions, and less frequently, MDM2 amplification. Secondary
glioblastomas develop in younger patients and often contain TP53
mutations as the earliest detectable alteration. These characteristics
are derived largely from patients selected on the basis of clinical
history and sequential biopsies. Currently available data are
insufficient for a substitution of histologic classification and grading
of astrocytic tumors by genetic typing alone. More subtypes of
glioblastomas may exist with intermediate clinical and genetic profiles,
a factor exemplified by the giant-cell glioblastoma that clinically and
genetically occupies a hybrid position between primary (de novo) and
secondary glioblastomas. Future research should aim at the
identification of criteria for a combined clinical, histologic, and
genetic classification of astrocytic tumors.
UI - 21435054
AU - Nozaki M; Tada M; Kobayashi H; Zhang CL; Sawamura Y; Abe H; Ishii N; Van
Roles of the functional loss of p53 and other genes in astrocytoma
tumorigenesis and progression.
SO - Neuro-oncol 1999 Apr;1(2):124-37
AD - Department of Neurosurgery, Cancer Institute, Hokkaido University School
of Medicine, Kitaku, Sapporo 060-8638, Japan.
Loss of function of the p53 tumor suppressor gene due to mutation occurs
early in astrocytoma tumorigenesis in about 30-40% of cases. This is
believed to confer a growth advantage to the cells, allowing them to
clonally expand due to loss of the p53-controlled G1 checkpoint and
apoptosis. Genetic instability due to the impaired ability of p53 to
mediate DNA damage repair further facilitates the acquisition of new
genetic abnormalities, leading to malignant progression of an
astrocytoma into anaplastic astrocytoma. This is reflected by a high
rate of p53 mutation (60-70%) in anaplastic astrocytomas. The cell cycle
control gets further compromised in astrocytoma by alterations in one of
the G1/S transition control genes, either loss of the p16/CDKN2 or RB
genes or amplification of the cyclin D gene. The final progression
process leading to glioblastoma multiforme seems to need additional
genetic abnormalities in the long arm of chromosome 10; one of which is
deletion and/or functional loss of the PTEN/MMAC1 gene. Glioblastomas
also occur as primary (de novo) lesions in patients of older age,
without p53 gene loss but with amplification of the epidermal growth
factor receptor (EGFR) genes. In contrast to the secondary glioblastomas
that evolve from astrocytoma cells with p53 mutations in younger
patients, primary glioblastomas seem to be resistant to radiation
therapy and thus show a poorer prognosis. The evaluation and design of
therapeutic modalities aimed at preventing malignant progression of
astrocytomas and glioblastomas should now be based on stratifying
patients with astrocytic tumors according to their genetic diagnosis.
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