26 research outputs found
Pituitary tumor transforming gene: An important gene in normal cellular functions and tumorigenesis
Pituitary tumor transforming gene (PTTG) is
an oncogene which is found to be highly expressed in
proliferating cells and in most of the tumors analyzed to
date. Overexpression of PTTG induces cellular
transformation and promotes tumor development in nude
mice. PTTG is regulated by various growth factors
including insulin and IGF-1. PTTG is a multifunctional
and multidomain protein. Some of the functions of
PTTG include inhibition of separation of sister
chromatids, expression and secretion of angiogenic and
metastatic factors. In this review we focus on expression
of PTTG in normal and tumor tissues, define its
biological function, its role in tumorigenesis, and its
interaction with other proteins that may play important
role in mediating tumorigenic function of PTTG
PTTG and cancer
Pituitary tumor transforming gene (pttg) is a
recently isolated oncogene that is expressed in most of
the tumors. Overexpression of pttg results in an increase
in cell proliferation, induces cell transformation in vitro,
and promotes tumor formation in nude mice. The gene
encodes a protein of 202 amino acids with no significant
homology with other known proteins. The protein is a
multi domain consisting of a transactivation domain,
domain required for ubiquitin-mediated proteolysis and a
DNA binding domain. pttg protein is bestowed with a
multitude of functions and seems to be involved in most
of the important mechanisms of cell proliferation,
differentiation and signaling. Given the number of
processes that are involved in the manifestation of
cancer, it thus becomes mandatory to study the role of
this potent oncogene in relation to the processes of cell
survival, death and functioning
The role of cancer stem cells and the side population in epithelial ovarian cancer
Ovarian cancer is the most lethal cancer of
the female reproductive tract, accounting for ~15,000
deaths per year according to the National Cancer
Institute and American Cancer Society. This review
article covers risk factors for the development of ovarian
cancer, current detection strategies, prognostic markers,
treatment strategies, etiology of tumorigenesis, and
ovarian somatic stem cells. While the etiology of ovarian
cancer is still unknown, several theories have been
proposed as the mechanism of carcinogenesis. One
theory states that the surface epithelium undergoing
invagination and forming inclusion cysts that are
exposed to growth factors and cytokines. The
“gonadotropin theory” has also been proposed. Other
reigning models for tumorigenesis include the
stochastical model where a distinct population of cells
acquires somatic mutations leading to metastasis, and the
hierarchical model where the tumor is initiated by cancer
stem cells (CSCs). CSCs isolated from primary tumors
have the ability to regenerate the tumor and reconstitute
the original tumor phenotype with as few as 100 cells.
CSCs from ovarian carcinomas display the cell surface
markers CD44+CD117+CD133+. CSCs are also thought
to account for chemotherapy resistance through the
expression of highly selective transporters ABCG2 and
MDR1 and activation of TLR4/MyD88. The side
population has been characterized by their ability to
efflux lipophilic substrates, including the dye Hoechst
33342 and many chemotherapy agents. This ability has
been attributed to the expression of the transporters
ABCG2 and MDR1
Identification of gene networks modulated by activin in LßT2 cells using DNA microarray analysis
Activins, members of the TGFß family of
proteins, are widely expressed in a variety of tissues.
First identified based on their ability to regulate
biosynthesis and secretion of follicle-stimulating
hormone (FSH), activins have also been shown to
modulate development, cell growth, apoptosis, and
inflammation. Despite their many known functions, the
precise mechanisms and downstream signaling pathways
by which activins mediate their diverse effects remain
unknown. We have used a DNA microarray assay to
identify genes that are regulated by activin, alone or in
combination with gonadotropin-releasing hormone
(GnRH), another major regulator of FSH, in a murine
gonadotrope-derived cell line (LßT2). We used mRNA
from these cells to screen Affymetrix Mu74av2 mouse
Gene Chip oligonucleotide microarrays, representing
approximately 12,400 mouse genes. Treatment of LßT2
cells with activin A, a gonadotropin-releasing hormone
agonist (GnRHA) or activin A plus GnRHA resulted in
alterations in levels of gene expression that ranged in
magnitude from 15 to 67-fold. Data analysis identified
268 transcripts that were up- or down-regulated by twofold
or more. Distinct sets of genes were affected by
treatment with activin, GnRHA and activin plus
GnRHA, suggesting interactions between activin and
GnRHA. Changes in expression of seven randomly
selected representative genes identified by the
microarray technique were confirmed by real-time
quantitative PCR and semi-quantitative reverse
transcription/PCR (RT/PCR). Modulation of expression
of genes by activin suggests that activin may mediate its
effects through a variety of signaling pathways
MicroRNA-21 Controls Circadian Regulation of Apoptosis in Atherosclerotic Lesions
Background: The necrotic core partly formed by ineffective efferocytosis increases the risk of an atherosclerotic plaque rupture. Microribonucleic acids contribute to necrotic core formation by regulating efferocytosis and macrophage apoptosis. Atherosclerotic plaque rupture occurs at increased frequency in the early morning, indicating diurnal changes in plaque vulnerability. Although circadian rhythms play a role in atherosclerosis, the molecular clock output pathways that control plaque composition and rupture susceptibility are unclear. Methods: Circadian gene expression, necrotic core size, apoptosis, and efferocytosis in aortic lesions were investigated at different times of the day in Apoe(-/-)Mir21(+/+) mice and Apoe(-/-)Mir21(-/-) mice after consumption of a high-fat diet for 12 weeks. Genome-wide gene expression and lesion formation were analyzed in bone marrow-transplanted mice. Diurnal changes in apoptosis and clock gene expression were determined in human atherosclerotic lesions. Results: The expression of molecular clock genes, lesional apoptosis, and necrotic core size were diurnally regulated in Apoe(-/-) mice. Efferocytosis did not match the diurnal increase in apoptosis at the beginning of the active phase. However, in parallel with apoptosis, expression levels of oscillating Mir21 strands decreased in the mouse atherosclerotic aorta. Mir21 knockout abolished circadian regulation of apoptosis and reduced necrotic core size but did not affect core clock gene expression. Further, Mir21 knockout upregulated expression of proapoptotic Xaf1 (XIAP-associated factor 1) in the atherosclerotic aorta, which abolished circadian expression of Xaf1. The antiapoptotic effect of Mir21 was mediated by noncanonical targeting of Xaf1 through both Mir21 strands. Mir21 knockout in bone marrow cells also reduced atherosclerosis and necrotic core size. Circadian regulation of clock gene expression was confirmed in human atherosclerotic lesions. Apoptosis oscillated diurnally in phase with XAF1 expression, demonstrating an early morning peak antiphase to that of the Mir21 strands. Conclusions: Our findings suggest that the molecular clock in atherosclerotic lesions induces a diurnal rhythm of apoptosis regulated by circadian Mir21 expression in macrophages that is not matched by efferocytosis, thus increasing the size of the necrotic core