1: Mol Cell Biol. 2005 Sep;25(17):7432-40. 

Role of Stat3 in regulating p53 expression and function.

Niu G, Wright KL, Ma Y, Wright GM, Huang M, Irby R, Briggs J, Karras J, Cress
WD, Pardoll D, Jove R, Chen J, Yu H.

Immunology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa,
FL 33612, USA.

Loss of p53 function by mutation is common in cancer. However, most natural p53
mutations occur at a late stage in tumor development, and many clinically
detectable cancers have reduced p53 expression but no p53 mutations. It remains
to be fully determined what mechanisms disable p53 during malignant initiation
and in cancers without mutations that directly affect p53. We show here that
oncogenic signaling pathways inhibit the p53 gene transcription rate through a
mechanism involving Stat3, which binds to the p53 promoter in vitro and in vivo.
Site-specific mutation of a Stat3 DNA-binding site in the p53 promoter partially
abrogates Stat3-induced inhibition. Stat3 activity also influences p53 response
genes and affects UV-induced cell growth arrest in normal cells. Furthermore,
blocking Stat3 in cancer cells up-regulates expression of p53, leading to
p53-mediated tumor cell apoptosis. As a point of convergence for many oncogenic
signaling pathways, Stat3 is constitutively activated at high frequency in a
wide diversity of cancers and is a promising molecular target for cancer
therapy. Thus, repression of p53 expression by Stat3 is likely to have an
important role in development of tumors, and targeting Stat3 represents a novel
therapeutic approach for p53 reactivation in many cancers lacking p53 mutations.

PMID: 16107692 [PubMed - indexed for MEDLINE]


---------------------------------------------------------------


2: Int J Gynecol Pathol. 2005 Jul;24(3):247-53. 

Survivin expression in endometrial carcinoma: a tissue microarray study with
correlation with PTEN and STAT-3.

Pallares J, Martinez-Guitarte JL, Dolcet X, Llobet D, Rue M, Palacios J, Prat J,
Matias-Guiu X.

Department of Pathology and Molecular Genetics, Hospital Universitari Arnau de
Vilanova, 25198 Lleida, Spain.

Evasion of apoptotic cell death plays a key role in cancer development. Survivin
is a member of the inhibitor of apoptosis proteins, which also has a role in the
control of cell division. Survivin may be overexpressed in some tumors and has
been suggested to be related to PTEN, beta-catenin, p53 [all of them frequently
abnormal in endometrial carcinomas (ECs)], and STAT-3. A tissue microarray was
constructed from paraffin-embedded blocks of 95 ECs, previously studied for
microsatellite instability and for alterations in PTEN, k-RAS, and CTNNB-1.
Immunohistochemical evaluation included 1) survivin, 2) markers of cell
proliferation and apoptosis (Ki67-MIB1 and M 30-neoepitope cytokeratin 18), and
3) proteins involved in cell signaling pathways (PTEN, phospho-AKT,
beta-catenin, p53, and STAT-3). Survivin expression was frequent in ECs (75.95%)
but did not show any statistical significant correlation with histological type
and grade, stage, overall survival, or mitotic and apoptotic indexes. Survivin
expression had a statistical significant correlation with decreased PTEN
expression (r = -0.383, p = 0.001), increased phospho-AKT (r = 0.70, p < 0.001),
and positive STAT-3 immunostaining (r = 0.6, p < 0.001). Survivin expression did
not show statistical correlation with either beta-catenin or p53 alterations.
The results suggest that increased survivin expression is frequent in ECs and
may be dependent on STAT-3 and PI3 K/AKT activation. Because PTEN abnormalities
are very frequent in ECs, the results from this study indicate that PTEN may
interfere with the process of apoptosis and cell proliferation by promoting
survivin expression.

PMID: 15968200 [PubMed - indexed for MEDLINE]


---------------------------------------------------------------


3: Oncogene. 2005 Apr 28;24(19):3083-90. 

p53 mediates a default programme of mammary gland involution in the absence of
STAT3.

Matthews JR, Clarke AR.

School of Biosciences, Cardiff University, Cardiff, UK.

Previous studies have demonstrated a proapoptotic role for the transcription
factor STAT3 in involuting murine mammary epithelium, resulting in delayed
involution and lower levels of apoptosis in the STAT3 null gland relative to
wild-type controls. As p53 was implicated in the eventual involution of the
STAT3 null gland, we examined the effect of STAT3 loss in the mammary gland in a
p53 null background. Combined loss of STAT3 and p53 severely perturbed
involution, with hyperdelayed loss of epithelium and reappearance of adipocytes.
The early apoptotic response was almost completely abrogated, although elevated
levels of delayed apoptosis persisted at days 6, 17 and 4 weeks of involution in
STAT3-p53 doubly null mammary glands. A 5.7-fold upregulation of the
cyclin-dependent kinase inhibitor p21Waf1 at 3 days of involution in STAT3 null
glands was abolished in STAT3-p53 doubly null glands -- suggesting that the
critical factor triggering delayed involution in the STAT3 null gland is a
p53-dependent rise in p21Waf1 levels around day 3 of involution. Further,
STAT3-p53 doubly null glands showed significantly higher levels of proliferation
compared to STAT3 or p53 singly null (or wild-type) glands at days 6, 17 and 4
weeks of involution. Combined loss of STAT3 and p53 therefore results in
hyperdelayed involution, demonstrating their synergistic physiological roles in
normal involution. This inappropriate retention of p53-deficient cells may
represent a novel mechanism of tumour predisposition.

PMID: 15735683 [PubMed - indexed for MEDLINE]


---------------------------------------------------------------


4: Eur J Clin Invest. 2005 Feb;35(2):140-7. 

Molecular events associated with accelerated proliferative response in rat
livers when partial hepatectomy is preceded by a sham operation.

Laurent S, Starkel P, Leclercq IA, Lambotte L, Maiter D, Horsmans Y.

Department of Gastroenterology, Universite Catholique de Louvain, 1200 Brussels,
Belgium.

BACKGROUND: When a sham operation is performed 6 h before partial hepatectomy
(PH), the regenerative response is accelerated suggesting that sham operation
itself contributes to cellular events leading to proliferation. MATERIALS AND
METHODS: In order to examine the mechanisms implicated in this acceleration, we
compared the activation of several factors associated with the progression
through the cell cycle at various times after PH and after PH preceded by sham
operation (S6 h + PH). The effect of a single sham (S) and two combined sham
operations (S6 h + S) was also examined. Nonoperated rats were used as controls
(C). RESULTS: The early factors NF-kappaB and Stat3 were activated after S6 h +
PH and S6 h + S. C-jun expression was increased 0.5 h and 2 h after PH and 6 h
after sham. There was no further increase in S6 h + PH and S6 h + S. In
contrast, c-myc expression returned to baseline levels after S6 h and a new
increase was observed 2 h after S6 h + PH but not after S6 h + S. P53 mRNA was
significantly expressed 6 h after S6 h + PH, but at a level similar than that
observed 6 and 12 h after PH alone. An earlier increase in c-Ha-ras mRNA and
cyclin E protein was found in S6 h + PH, in comparison with PH alone.
CONCLUSIONS: The first divergent response between the two combined models
involved c-myc expression. However, major differences related to the accelerated
liver regenerative response observed after S6 h + PH were found at late time
points associating an earlier expression of c-Ha-ras and nuclear cyclin E.

PMID: 15667586 [PubMed - indexed for MEDLINE]


---------------------------------------------------------------


5: Cancer Res. 2004 Dec 15;64(24):9105-14. 

Elimination of hepatic metastases of colon cancer cells via p53-independent
cross-talk between irinotecan and Apo2 ligand/TRAIL.

Ravi R, Jain AJ, Schulick RD, Pham V, Prouser TS, Allen H, Mayer EG, Yu H,
Pardoll DM, Ashkenazi A, Bedi A.

The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns
Hopkins University School of Medicine, Baltimore, Maryland, USA.

The majority of colorectal cancers have lost/inactivated the p53 tumor
suppressor gene. Using isogenic human colon cancer cells that differ only in
their p53 status, we demonstrate that loss of p53 renders tumor cells relatively
resistant to the topoisomerase I inhibitor, irinotecan. Whereas
irinotecan-induced up-regulation of the proapoptotic proteins PUMA and Noxa
requires p53, we find that irinotecan inhibits Janus kinase 2 (JAK2)-signal
transducer and activator of transcription 3 and 5 (STAT3/5) signaling in both
p53-proficient and p53-deficient tumor cells. We show that irinotecan inhibits
JAK2-STAT3/5-dependent expression of survival proteins (Bcl-x(L) and XIAP) and
cooperates with Apo2 ligand/tumor necrosis factor-related apoptosis-inducing
ligand (Apo2L/TRAIL) to facilitate p53-independent apoptosis of colon cancer
cells. Whereas xenografts of p53-deficient colon cancer cells are relatively
resistant to irinotecan compared with their p53-proficient counterparts,
combined treatment with irinotecan and Apo2L/TRAIL eliminates hepatic metastases
of both p53-proficient and p53-deficient cancer cells in vivo and significantly
improves the survival of animals relative to treatment with either agent alone.
Although the synergy between chemotherapy and Apo2L/TRAIL has been ascribed to
p53, our data demonstrate that irinotecan enhances Apo2L/TRAIL-induced apoptosis
of tumor cells via a distinct p53-independent mechanism involving inhibition of
JAK2-STAT3/5 signaling. These findings identify a novel p53-independent channel
of cross-talk between topoisomerase I inhibitors and Apo2L/TRAIL and suggest
that the addition of Apo2L/TRAIL can improve the therapeutic index of irinotecan
against both p53-proficient and p53-deficient colorectal cancers, including
those that have metastasized to the liver.

PMID: 15604280 [PubMed - indexed for MEDLINE]


---------------------------------------------------------------


6: Biochem Biophys Res Commun. 2004 Aug 20;321(2):441-7. 

Modulation of Janus kinase 2 by p53 in ovarian cancer cells.

Reid T, Jin X, Song H, Tang HJ, Reynolds RK, Lin J.

Cellular and Molecular Biology Graduate Program, Division of Gynecologic
Oncology, Department of Obstetrics and Gynecology, University of Michigan
Comprehensive Cancer Center, Ann Arbor, MI 48109-0936, USA.

The constitutive activation of the Janus kinase 2 (JAK2) and mutation of the p53
tumor suppressor are both detected in human cancer. We examined the potential
regulation of JAK2 phosphorylation by wild-type (wt) p53 in human ovarian cancer
cell lines, Caov-3 and MDAH2774, which harbor mutant form of p53 tumor
suppressor gene and high levels of phosphorylated JAK2. The wt p53 gene was
re-introduced into the cells using an adenovirus vector. In addition to wt p53,
mutant p53 22/23, mutant p53-175, and NCV (negative control virus) were
introduced into the cells in the control groups. Expression of wt p53, but not
that of p53-175 mutant, diminished JAK2 tyrosine phosphorylation in MDAH2774 and
Caov-3 cell lines. Expression of wt p53 or p53 22/23 mutant did not cause a
reduction in the phosphorylation of unrelated protein kinases, ERK1 and ERK2
(ERK1/2). The inhibition of JAK2 tyrosine phosphorylation can be reversed by
tyrosine phosphatase inhibitor, sodium orthovanadate. Protein tyrosine
phosphatase 1-B levels increased with introduction of wt p53 and may be involved
in the dephosphorylation of JAK2. These findings present a possible
p53-dependent cellular process of modulating JAK2 tyrosine phosphorylation in
ovarian cancer cell lines.

PMID: 15358195 [PubMed - indexed for MEDLINE]


---------------------------------------------------------------


7: Zhejiang Da Xue Xue Bao Yi Xue Ban. 2004 Jul;33(4):331-4. 

[Effect of STAT3 phosphorylation and p53 expression on human epidermal non 
melanoma cutaneous tumors]

[Article in Chinese]

Cai SQ, Chen LR, Wang HJ, Yao LF, Zheng M.

Department of Dermatology, the Second Affiliated Hospital, College of Medicine,
Zhejiang University, Hangzhou 310009, China. clear-water@sohu.com

OBJECTIVE: To investigate the effect of stat3 phosphorylation and p53 expression
on human epidermal non-melanoma cutaneous tumours. METHODS: Immunohistochemistry
technique was employed to measure the expression of p-stat3 and p53 protein in
skin tissue from 30 cases of skin squamous cell carcinoma (SCC), 20 cases of
basal cell carcinoma (BCC), 20 cases of seborrhoeic keratosis (SK) and 20 normal
subjects. RESULT: (1) p-stat3 protein was abnormally increased in SCC and BCC as
compared with normal skin and SK. Expression of p-stat3 in SCC was also
significantly higher than that in BCC. (2) Expression of p-stat3 was higher in
poorly-differentiated cancers than that in well-differentiated cancers in SCC.
The positive rate of p-stat3 expression was correlated with the depth of tumor
invasion, but not with tumor size. (3) There was no p53 protein expression on
normal skin and SK, it was significantly upregulated in SCC and BCC. In SCC, the
intensity of p53 expression was associated with tumor differentiation. There was
no correlation between the positive rate of p53 expression and the depth of
tumor invasion, whereas the positive rate of p53 expression was correlated with
the sun-exposure area. (4) There existed positive correlation between the
expression intensity of p-stat3 and p53 in SCC (r=0.641, P<0.05). CONCLUSION:
(1) The overexpression of p-stat3 may play an important role in the development
of epidermal tumors. (2) The abnormal activation of stat3 may be related to
metastatic potentials in SCC. (3) Both p53 gene and stat3 may contribute to the
pathogenesis of skin SCC.

PMID: 15269985 [PubMed - indexed for MEDLINE]


---------------------------------------------------------------


8: Cell Signal. 2004 Oct;16(10):1085-104. 

Nuclear bodies and compartments: functional roles and cellular signalling in
health and disease.

Zimber A, Nguyen QD, Gespach C.

Department of Animal Sciences, Faculty of Agriculture, The Hebrew University of
Jerusalem, Rehovot 76100, Israel.

There is much interest in recent years in the possible role of different nuclear
compartments and subnuclear domains in the regulation of gene expression,
signalling, and cellular functions. The nucleus contains inositol phosphates,
actin and actin-binding proteins and myosin isoforms, multiple protein kinases
and phosphatases targeting Cdk-1 and Cdk-2, MAPK/SAPK, and Src-related kinases
and their substrates, suggesting the implication of several signalling pathways
in the intranuclear organization and function of nuclear bodies (NBs). NBs
include the well-characterized Cajal bodies (CBs; or coiled bodies), the
nucleolus, perinucleolar and perichromatin regions, additional NBs best
illustrated by the promyelocytic leukemia nuclear bodies [PML-NBs, also named
PML oncogenic dots (PODs), ND10, Kr-bodies] and similar intranuclear foci
containing multi-molecular complexes with major role in DNA replication,
surveillance, and repair, as well as messenger RNA and ribosomal RNA synthesis
and assembly. Chromatin modifying proteins, such as the CBP acetyltransferase
and type I histone deacetylase, accumulate at PML-NBs. PML-NBs and Cajal bodies
are very dynamic and mobile within the nuclear space and are regulated by
cellular stress (heat shock, apoptosis, senescence, heavy metal exposure, viral
infection, and DNA damage responses). NBs strongly interact, using signalling
mechanisms for the directional and ordered traffic of essential molecular
components. NBs organize the delivery and storage of essential RNAs and proteins
that play a role in transcription, pre-mRNA biosynthesis and splicing, and the
sequestration and/or degradation of regulatory proteins, such as heterogenous
nuclear ribonuclear proteins (hnRNPs), p53, Rb1, CBP, STAT3, and others. The
objective of this review is to summarize some aspects of these nuclear
structures/bodies/domains, including their proposed roles in cellular signalling
and in human diseases, mainly neurodegenerative disorders and cancer.

Publication Types:
    Review
    Review, Tutorial

PMID: 15240004 [PubMed - indexed for MEDLINE]


---------------------------------------------------------------


9: J Biol Chem. 2003 Dec 19;278(51):50915-22. Epub 2003 Oct 13. 

Increased expression of Bcl-xL and c-Myc is associated with transformation by
Abelson murine leukemia virus.

Noronha EJ, Sterling KH, Calame KL.

Department of Microbiology, Columbia University College of Physicians and
Surgeons, New York, New York 10032, USA.

Transformation mediated by the v-Abl oncoprotein, a tyrosine kinase encoded by
the Abelson murine leukemia virus, is a multi-step process requiring genetic
alterations in addition to expression of v-Abl. Loss of p53 or p19ARF was
previously shown to be required for Abelson murine leukemia virus transformation
of primary mouse embryonic fibroblasts (MEFs). By comparing gene expression
patterns in primary p53-/- MEFs acutely infected with the v-Abl retrovirus,
v-Abl-transformed MEF clones, and v-Abl-transformed MEF clones treated with Abl
kinase inhibitor STI 571, we have identified additional genetic alterations
associated with v-Abl transformation. Bcl-xL mRNA was elevated in three of five
v-Abl-transformed MEF clones. In addition, elevated expression of c-Myc mRNA,
caused either by c-myc gene amplification or by enhanced signaling via STAT3,
was observed in five v-Abl-transformed MEF clones. The data suggest that
increases in cell survival associated with Bcl-xL and increases in cell growth
associated with c-Myc facilitate the transformation process dependent on
constitutive mitogenic signaling by v-Abl.

PMID: 14559912 [PubMed - indexed for MEDLINE]


---------------------------------------------------------------


10: Cell Cycle. 2003 Jul-Aug;2(4):293-5. 

New targets for viral cyclins.

Coqueret O.

INSERM U564, 4 rue Larrey, CHU Angers, 49033 Angers Cedex, France.
olivier.coqueret@univ-angers.fr

It is now clear that viral cyclins have new functions that provide infected
cells with additional stimuli that further activate cell cycle progression.
These proteins resist the actions of cell cycle inhibitors, extend the range of
cdk substrates, and as a consequence favor cell proliferation and virus
propagation. Like some of the endogeneous cyclins, these viral proteins might
have also important functions during transcriptional regulation. Binding to
transcriptional regulator might enable the virus to target multiple functions of
transcriptional activation and cell growth. Whether these effects have any
physiological relevance during viral replication or cell transformation will be
an important issue to address.

Publication Types:
    Review
    Review, Tutorial

PMID: 12851476 [PubMed - indexed for MEDLINE]


---------------------------------------------------------------


11: Curr Opin Pharmacol. 2003 Jun;3(3):317-22. 

The role of apoptosis in rheumatoid arthritis.

Liu H, Pope RM.

Northwestern University Feinberg School of Medicine and the VA Medical Center,
Chicago, Lakeside Division Department of Medicine, Division of Rheumatology, 303
East Chicago Avenue, Tarry 3-377, Chicago IL 60611, USA.

Rheumatoid arthritis (RA) is a chronic inflammatory disease, which results in
inflammation of the synovial lining and destruction of the adjacent bone and
cartilage. Synovial macrophages, fibroblasts and lymphocytes are critical to the
pathogenesis of this disease, in which apoptosis may play divergent roles. In
joints of patients with active RA, few apoptotic cells are detected, and
experimental data suggest that enhanced apoptosis within the joint might be
therapeutically beneficial. Signaling pathways, such as the nuclear factor
kappa-B, phosphatidylinositol 3-kinase/Akt-1 and signal transducer and activator
of transcription-3 pathways, are highly activated in the RA joint. Activation of
these pathways contributes not only to the expression of genes that cause
inflammation and destruction but also to the expression of a variety of
anti-apoptotic molecules, including FLICE inhibitory protein, Bcl-2, and Mcl-1,
which protect against apoptosis that may be initiated through death receptor- or
mitochondria-dependent pathways. The induction of apoptosis of macrophages,
synovial fibroblasts or lymphocytes, either through suppression of signaling
pathways or inhibition of the expression of anti-apoptotic molecules, could be
therapeutically beneficial in RA. While tumour necrosis factor-alpha contributes
to inflammation, destruction and protection against apoptosis in the RA joint
(together with FasL), it also promotes apoptosis of bone marrow progenitor cells
that contribute to anemia of chronic disease, which is very common in acute RA.

Publication Types:
    Review
    Review, Tutorial

PMID: 12810199 [PubMed - indexed for MEDLINE]


---------------------------------------------------------------


12: Oncogene. 2003 May 19;22(20):3152-61. 

Death receptors and melanoma resistance to apoptosis.

Ivanov VN, Bhoumik A, Ronai Z.

Ruttenberg Cancer Center, Mount Sinai School of Medicine, New York, NY 10029,
USA.

Impaired ability to undergo programmed cell death in response to a wide range of
external stimuli acquires melanomas a selective advantage for progression and
metastasis as well as their notorious resistance to therapy. Better
understanding of mechanisms that govern apoptosis has enabled identification of
diverse routes by which melanomas manage to escape stimuli of apoptosis. Changes
at genomic, transcriptional and post-translational levels of G-proteins and
protein kinases (Ras, B-Raf) and their transcription factor effectors (c-Jun,
ATF2, Stat3 and NF-kappaB) affects TNF, Fas and TRAIL receptors, which play
important roles in acquiring melanoma's resistance to apoptosis. Here, we
summarize our current understanding of changes that alters the regulation of
death receptors during melanoma development.

Publication Types:
    Review
    Review, Tutorial

PMID: 12789291 [PubMed - indexed for MEDLINE]


---------------------------------------------------------------


13: Gastroenterology. 2002 Dec;123(6):2052-63. 

Stat3 and NF-kappaB activation prevents apoptosis in pancreatic carcinogenesis.

Greten FR, Weber CK, Greten TF, Schneider G, Wagner M, Adler G, Schmid RM.

Internal Medicine II, Technical University of Munich, Germany.

BACKGROUND & AIMS: Human pancreatic adenocarcinoma has an overall poor
prognosis. Therapeutic efforts are often ineffective because of late diagnosis
and a high degree of chemoresistance. Overexpression of transforming growth
factor alpha in the pancreas of transgenic mice causes the formation of
premalignant ductal lesions and the development of invasive ductal
adenocarcinoma. The aim of the present study was to explore regulation of
proapoptotic and antiapoptotic signals during pancreatic tumor development in
mice. METHODS: EL-TGFalpha-hGH transgenic mice crossbred to p53-deficient mice
develop ductal pancreatic adenocarcinoma resembling the human disease. During
the multistep carcinogenesis up-regulation of Bcl-x(L) is evident early and
persists throughout tumorigenesis as detected by Real Time PCR, Western blot
analysis, and immunofluorescence. RESULTS: Up-regulation of Bcl-x(L) is evident
early in tumor development and persists throughout tumorigenesis. The
transcription factors Stat3 and NF-kappaB induce increased Bcl-x(L) expression
in the premalignant lesions and tumor cells. Inhibition of either transcription
factor alone leads to Bcl-x(L) down-regulation in transient transfection assays.
Functional analysis shows that blocking of both Stat3 and NF-kappaB together
induces programmed cell death in murine pancreatic tumor cells. CONCLUSIONS:
These findings indicate that apoptosis resistance precedes formation of invasive
pancreatic cancer. Therefore, combined inhibition of Stat3 and NF-kappaB might
represent a novel strategy for tumor prevention and therapy.

PMID: 12454861 [PubMed - indexed for MEDLINE]


---------------------------------------------------------------


14: J Dairy Sci. 2002 May;85(5):1103-10. 

Regulation of apoptosis during mammary involution by the p53 tumor suppressor
gene.

Jerry DJ, Dickinson ES, Roberts AL, Said TK.

Department of Veterinary & Animal Sciences, University of Massachusetts, Amherst
01003, USA. jjerry@vasci.umass.edu

Regulation and functions of the p53 tumor suppressor gene have been studied
extensively with respect to its critical role in maintaining the stability of
genomic DNA following genotoxic insults. However, p53 is also induced by
physiologic stimuli resulting in cell cycle arrest and apoptosis. In other
situations, the activity of p53 must be repressed to prevent inappropriate
removal of cells. The mammary gland provides a valuable system in which to study
the mechanisms by which the expression and biological responses to p53 can be
regulated under a variety of physiological circumstances. The pro-apoptotic role
of p53 in the secretory mammary epithelium may be especially relevant to
lactation in livestock. We have utilized p53-deficient mice to establish the
molecular targets of p53 in the mammary gland and biological consequences when
it is absent. The p21/WAF1 gene (Cdkn1a) is a transcriptional target gene of the
p53 protein that responds to elevated levels of p53 during milk stasis providing
an endogenous reporter of p53 activity. Abrogation of p53 resulted in delayed
involution of the mammary epithelium, demonstrating the physiological role of
p53 in regulating involution. Though delayed, stromal proteases were induced in
the mammary gland by 5 d postweaning, providing a p53-independent mechanism that
resulted in removal of the residual secretory epithelium. These processes can be
interrupted by treatment with hydrocortisone. These data establish p53 as a
physiological regulator of involution that acts to rapidly initiate apoptosis in
the secretory epithelium in response to stress signals, but also indicate the
presence of compensatory pathways to effect involution. Additional mechanisms
involving intracellular stress signaling pathways (e.g., Stat3) and
stromal-mediated pathways have been identified and, together with p53 pathways,
may be used to identify animals with greater persistency of lactation.

Publication Types:
    Review
    Review, Tutorial

PMID: 12086044 [PubMed - indexed for MEDLINE]


---------------------------------------------------------------


15: Oncogene. 2002 May 2;21(19):3082-8. 

p53 regulates Stat3 phosphorylation and DNA binding activity in human prostate
cancer cells expressing constitutively active Stat3.

Lin J, Tang H, Jin X, Jia G, Hsieh JT.

Division of Gynecologic Oncology, Department of Obstetrics and Gynecology,
University of Michigan Comprehensive Cancer Center, Ann Arbor, MI 48109-0936,
USA. linjia@mich.edu

Constitutive activation of the signal transducer and activator of transcription
3 (Stat3) and mutation of the p53 are both commonly detected in human prostate
cancer cells. We sought to investigate whether there is functional regulation of
Stat3 by wild-type (wt) p53. Our results demonstrate that expression of wt p53
but not mutant p53 significantly reduced tyrosine phosphorylation of Stat3 and
inhibited Stat3 DNA binding activity in both DU145 and Tsu prostate cancer cell
lines that express constitutively active Stat3. Expression of the p53 downstream
target, p21(WAF-1), did not have any inhibitory effect on Stat3 phosphorylation.
Wt p53 but not p21(WAF-1) induced dramatic apoptosis in these prostate cancer
cells. Expression of wt p53 did not cause a reduction of
phosphorylation-independent Stat3 protein and reduction of phosphorylation of
three unrelated protein kinases, ERK1, ERK2 (ERK1/2), and AKT. Interestingly,
p53-dependent apoptosis occurred in the presence of high levels of
phosphorylated AKT and ERK1/2 in both DU145 and Tsu prostate cancer cells.
Further, we evaluated a series of established human prostate, breast, and
ovarian cancer cell lines and found that all cancer cell lines expressing
constitutively active Stat3, only harbor mutated or deleted p53. One implication
of these results is that the anti-proliferative activities of p53 may not be
compatible with the constitutive Stat3 signal in cancer cells.

PMID: 12082540 [PubMed - indexed for MEDLINE]


---------------------------------------------------------------


16: Cancer Res. 2002 Jan 15;62(2):376-80. 

Modulation of signal transducer and activator of transcription 3 activities by
p53 tumor suppressor in breast cancer cells.

Lin J, Jin X, Rothman K, Lin HJ, Tang H, Burke W.

Division of Gynecologic Oncology, Department of Obstetrics and Gynecology,
University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan
48109-0936, USA. linjia@umich.edu

The constitutive activation of the Stat3 oncogene product and mutation of the
p53 tumor suppressor are both frequently detected in human breast cancer. We
sought to determine whether there is functional regulation of Stat3 by wild-type
(wt) p53. We demonstrate that expression of wt p53, but not mutant p53,
significantly diminished phosphorylation of Stat3, reduced Stat3 DNA binding
activity, and inhibited Stat3-dependent transcriptional activity in breast
cancer cells expressing constitutively active Stat3. Expression of wt p53 did
not cause a reduction in the phosphorylation of three unrelated protein kinases
in other signal transduction pathways, AKT, extracellular signal-regulated
kinase (ERK)1, and ERK2 or a reduction of phosphorylation of epidermal growth
factor receptor. Furthermore, the expression of the p53 downstream target,
p21(WAF-1), did not have an inhibitory effect on Stat3 phosphorylation. Wt p53
also induced significant apoptosis in breast cancer cell lines that express
constitutively active Stat3. Interestingly, the p53-dependent apoptosis occurred
in the presence of high levels of phosphorylated AKT and ERK1/2. Therefore,
these findings demonstrate a novel p53-dependent cellular process that regulates
Stat3 phosphorylation and activity.

PMID: 11809683 [PubMed - indexed for MEDLINE]


---------------------------------------------------------------


17: Int J Oncol. 2001 Dec;19(6):1155-60. 

EGFR dependent expression of STAT3 (but not STAT1) in breast cancer.

Berclaz G, Altermatt HJ, Rohrbach V, Siragusa A, Dreher E, Smith PD.

Department of Obstetrics and Gynecology, Inselspital, CH-3012 Berne,
Switzerland. gilles.berclaz@insel.ch

STAT proteins constitute a family of transcription factors whose activation by
cytokine and non-cytokine receptors leads to tyrosine phosphorylation,
dimerization and translocation from the cytoplasm to the nucleus. In the nucleus
they activate the transcription of specific genes by binding to consensus DNA
elements. STATs 1 and 3 can be activated by both cytokine and non-cytokine
receptors, and bind as homodimers or heterodimers to viral simian sarcoma virus
(sis)-inducible elements such as that found in the c-fos promoter. Activation of
c-Src and EGF receptor tyrosine kinases is associated with progression of breast
cancer. Both these events lead to activation of STAT proteins, Src kinases
activate STAT3 dependent transcription in mammary epithelial cells and EGF
receptor activation can lead to activation of STATs 1 and 3. STAT3 activation
has been demonstrated to have a role in oncogenesis and increasingly, activated
STAT proteins are found to be activated in human cancer. In this study we
describe detailed immunohistochemical analysis of nuclear and cytoplasmic STATs
1 and 3 expression in primary breast carcinomas and correlate this with EGFR,
HER2, p53, ER, PR, p21/waf1, Bcl-XL and Ki-67 expression. We also compared
expression between normal and tumor tissue. We report here a highly significant
correlation between nuclear STAT3 expression and breast cancers compared to
normal tissue. We also report a very strong correlation between nuclear STAT3
and EGFR expression in breast cancers. These data clearly demonstrate a strong
association between STAT3 activation and breast tumorigenesis and strengthen the
assertion that STAT3 activation may play an important role in the tumorigenic
conversion of breast tissue mediated by tyrosine kinase signaling pathways.

PMID: 11713584 [PubMed - indexed for MEDLINE]


---------------------------------------------------------------


18: Lab Invest. 2001 Sep;81(9):1299-307. 

Expression of presumed specific early and late factors associated with liver
regeneration in different rat surgical models.

Laurent S, Otsuka M, De Saeger C, Maiter D, Lambotte L, Horsmans Y.

Gastroenterology Laboratories, Universite Catholique de Louvain, Brussels,
Belgium.

Experiments performed on the portal branch ligation (PBL) model indicate that
early changes observed after surgery are not related to the regenerative process
because they also occur in atrophying lobes. To further confirm the lack of
specificity of the early events and to exclude the influence of circulatory
factors released by proliferating lobes on their occurrence, we investigated
this response after sham operation (SO) and portacaval shunt (PCS), a model
characterized by liver atrophy. We also attempted to determine expression of
later events associated specifically with regeneration, ie, expression of p53 or
c-Ha-ras, or inhibition of proliferation, ie, interleukin-1beta (IL-1beta) and
transforming growth factor-beta1 (TGF-beta1) after partial (PH) and temporary
partial (TPH) hepatectomy, SO and PCS. Nuclear factor-kappaB (NF-kappaB) and
signal transducer and activator of transcription 3 (STAT3) DNA binding were
assessed by electrophoretic mobility shift assay (EMSA), interleukin-6 (IL-6)
mRNA by reverse transcription-polymerase chain reaction (RT-PCR), c-myc and
c-jun mRNAs by Northern blot analysis at 0.5 and 2 hours, p53 and c-Ha-ras mRNAs
by Northern blot analysis at 8 and 24 hours, and IL-1beta and TGF-beta1 by
RT-PCR at 24 hours. The early response including an increase of NF-kappaB,
STAT3, IL-6, and immediate-early genes expression was present after PH, PCS, and
SO. In SO, slight differences were observed in comparison with PH: no NF-kappaB
p65/p50 DNA binding was observed, only three of six SO rats were positive for
IL-6, and immediate-early genes induction showed differences in the intensity of
the response. At later times, p53 mRNA increased at 8 hours after PH and TPH,
c-Ha-ras mRNA at 24 hours after PH, and IL-1beta mRNA at 24 hours after PCS.
Early events are not specifically associated with the reduction of liver mass or
with the regenerative process, are not predictive of future cell fate, and are
most likely related to surgical stress. p53 and c-Ha-ras induction is closely
associated with cell cycle progression whereas IL-1beta, but not TGF-beta1,
appears to be one of the negative growth regulators that might play an important
role in atrophy.

PMID: 11555677 [PubMed - indexed for MEDLINE]


---------------------------------------------------------------


19: Mol Cell Biol. 2000 Dec;20(24):9271-80. 

v-Src generates a p53-independent apoptotic signal.

Webb BL, Jimenez E, Martin GS.

Department of Molecular and Cell Biology, University of California at Berkeley,
Berkeley, California 94720, USA.

Evasion of apoptosis appears to be a necessary event in tumor progression. Some
oncogenes, such as c-myc and E1A, induce apoptosis in the absence of survival
factors. However, others, such as bcl-2 and v-src, activate antiapoptotic
pathways. For v-Src, these antiapoptotic pathways are dependent on the function
of Ras, phosphatidylinositol (PI) 3-kinase, and Stat3. Here we asked whether
v-Src can activate a proapoptotic signal when survival signaling is inhibited.
We show that when the functions of Ras and PI 3-kinase are inhibited,
v-src-transformed Rat-2 fibroblasts undergo apoptosis, evidenced by loss of
adherence, nuclear fragmentation, and chromosomal DNA degradation. The apoptotic
response is dependent on activation of caspase 3. Under similar conditions
nontransformed Rat-2 cells undergo considerably lower levels of apoptosis.
Apoptosis induced by v-Src is accompanied by a loss of mitochondrial membrane
potential and release of cytochrome c and is blocked by overexpression of bcl-2,
indicating that it is mediated by the mitochondrial pathway. However apoptosis
induced by v-Src is not accompanied by an increase in the level of p53 and is
not dependent on p53 function. Thus v-Src generates a p53-independent
proapoptotic signal.

PMID: 11094078 [PubMed - indexed for MEDLINE]


---------------------------------------------------------------


20: Genes Dev. 1999 Oct 1;13(19):2604-16. 

Suppression of epithelial apoptosis and delayed mammary gland involution in mice
with a conditional knockout of Stat3.

Chapman RS, Lourenco PC, Tonner E, Flint DJ, Selbert S, Takeda K, Akira S,
Clarke AR, Watson CJ.

Cancer Research Campaign (CRC) Laboratories, Department of Pathology, University
of Edinburgh, Medical School, Edinburgh EH8 9AG UK.

Mammary gland involution is characterized by extensive apoptosis of the
epithelial cells. At the onset of involution, Stat3 is specifically activated.
To address the function of this signaling molecule in mammary epithelial
apoptosis, we have generated a conditional knockout of Stat3 using the Cre-lox
recombination system. Following weaning, a decrease in apoptosis and a dramatic
delay of involution occurred in Stat3 null mammary tissue. Involution is
normally associated with a significant increase in IGFBP-5 levels. This was
observed in control glands, but not in the absence of Stat3. IGFBP-5 has been
suggested to induce apoptosis by sequestering IGF-1 to casein micelles, thereby
inhibiting its survival function. Our findings suggest that IGFBP-5 is a direct
or indirect target for Stat3 and its upregulation is essential to normal
involution. No marked differences were seen in the regulation of Stat5,
Bcl-x(L), or Bax in the absence of Stat3. Precocious activation of Stat1 and
increases in levels of p53 and p21 occurred and may act as compensatory
mechanisms for the eventual initiation of involution observed in Stat3 null
mammary glands. This is the first demonstration of the importance of a Stat
factor in signaling the initiation of physiological apoptosis in vivo.

PMID: 10521404 [PubMed - indexed for MEDLINE]


---------------------------------------------------------------


21: J Biol Chem. 1998 Aug 14;273(33):21137-44. 

Transcriptional activation of the p21(WAF1,CIP1,SDI1) gene by interleukin-6 type
cytokines. A prerequisite for their pro-differentiating and anti-apoptotic
effects on human osteoblastic cells.

Bellido T, O'Brien CA, Roberson PK, Manolagas SC.

Division of Endocrinology and Metabolism, the Center for Osteoporosis and
Metabolic Bone Diseases, University of Arkansas for Medical Sciences, Little
Rock, AR 72205, USA. tmbellido@life.uams.edu

The cyclin-dependent kinase inhibitor p21(WAF1,CIP1,SDI1) plays a critical role
in cell differentiation, and it has been shown to confer resistance to
apoptosis. Based on this, and on evidence that activation of the gp130/signal
transducer and activator of transcription (STAT) signal transduction pathway by
interleukin (IL)-6 type cytokines promotes differentiation and prevents
apoptosis in osteoblastic cells, we have investigated the possibility that p21
is a downstream effector of this signaling pathway in osteoblasts. We report
that either oncostatin M (OSM) or IL-6 plus soluble IL-6 receptor increased the
levels of p21 mRNA and protein in the osteoblast-like human osteosarcoma cell
line MG63 and stimulated the activity of a 2.4-kilobase pair segment of the
human p21 gene promoter. Further, nuclear extracts from cytokine-stimulated MG63
cells formed protein-DNA complexes with a 19-base pair nucleotide fragment of
the p21 promoter containing a single STAT response element. The identity of the
binding proteins as Stat3 and Stat1 was demonstrated with specific antibodies.
In addition, and in support of a mediating role of STATs in the activation of
the p21 promoter, overexpression of Stat3 potentiated the cytokine effect on the
p21 promoter; whereas a dominant negative Stat3, or a mutation of the STAT
response element on the promoter, significantly reduced the cytokine effect.
Finally, antisense oligonucleotides complementary to p21 mRNA inhibited
OSM-induced stimulation of alkaline phosphatase expression and antagonized the
protective effect of OSM on anti-Fas-induced apoptosis. These results
demonstrate that p21 is a downstream effector of gp130/Stat3 activation and a
critical mediator of the pro-differentiating and anti-apoptotic effects of IL-6
type cytokines on human osteoblastic cells.

PMID: 9694869 [PubMed - indexed for MEDLINE]


---------------------------------------------------------------


22: J Immunol. 1998 Jul 1;161(1):325-34. 

Regulation of IL-6 signaling by p53: STAT3- and STAT5-masking in
p53-Val135-containing human hepatoma Hep3B cell lines.

Rayanade RJ, Ndubuisi MI, Etlinger JD, Sehgal PB.

Department of Cell Biology and Anatomy, New York Medical College, Valhalla
10595, USA.

The influence of p53 on cytokine-triggered Janus kinase-STAT signaling was
investigated in human hepatoma Hep3B cell lines engineered to constitutively
express the temperature-sensitive Val135 mutant of p53. In comparison to the
parental p53-free Hep3B cells, these p53-Val135-containing Hep3B cell lines
displayed a reduced response to IL-6 at the wild-type-like p53 temperature (32.5
degrees C). In these cells, IL-6 induced a marked reduction in the immunologic
accessibility of cytoplasmic and nuclear STAT3 and STAT5 within 20 to 30 min
that lasted 2 to 4 h (STAT-masking) provided that the cells had been previously
cultured at 32.5 degrees C for at least 18 to 20 h. The onset of IL-6-induced
STAT-masking required protein tyrosine kinase, protein tyrosine phosphatase,
proteasomal, phospholipase C, and mitogen-activated protein kinase kinase 1
activities. The maintenance of IL-6-induced STAT-masking was dependent on
continued signaling through the phosphatidylinositol-dependent phospholipase C
pathway. Despite a reduction in IL-6-induced STAT3 DNA binding activity in the
nuclear compartment during STAT-masking, there was increased and prolonged
accumulation of tyrosine-phosphorylated STAT3 in both the cytoplasmic and
nuclear compartments, indicating that the capacity of tyrosine-phosphorylated
STAT3 to bind DNA was reduced during STAT-masking. Thus, IL-6-induced
STAT-masking, as dramatically evident on immunomicroscopy, is a visible
consequence of a novel cellular process by which a p53-Val135-induced gene
product(s) regulates the association of masking protein(s) with and the
DNA-binding capacity of STAT3.

PMID: 9647240 [PubMed - indexed for MEDLINE]


---------------------------------------------------------------


23: J Biol Chem. 1997 Feb 21;272(8):4659-62. 

Proteasome- and p53-dependent masking of signal transducer and activator of
transcription (STAT) factors.

Rayanade RJ, Patel K, Ndubuisi M, Sharma S, Omura S, Etlinger JD, Pine R, Sehgal
PB.

Department of Cell Biology & Anatomy, New York Medical College, Valhalla, New
York 10595, USA.

Hepatoma Hep3B cell lines stably expressing a temperature-sensitive p53 species
(p53-Val-135) displayed a reduced response to interleukin-6 (IL-6) when cultured
at the wild-type (wt) p53 temperature (Wang, L., Rayanade, R., Garcia, D.,
Patel, K., Pan, H., and Sehgal, P. B. (1995) J. Biol. Chem. 270, 23159-23165).
We now report that in such cultures IL-6 caused a rapid (20-30 min) and marked
loss of cellular immunostaining for STAT3 and STAT5, but not for STAT1. The loss
of STAT3 and STAT5 immunostaining was transient (lasted 120 min) and tyrosine
kinase-dependent, and even though the loss was blocked by the proteasome
inhibitors MG132 and lactacystin it was not accompanied by changes in cellular
levels of STAT3 and STAT5 proteins suggesting that IL-6 triggered a rapid
masking but not degradation of these transcription factors. STAT3 and STAT5
masking was accompanied by a reduction in IL-6-induced nuclear DNA-binding
activity. The data suggest that p53 may influence Jak-STAT signaling through a
novel indirect mechanism involving a wt p53-dependent gene product which upon
cytokine addition is activated into a "STAT-masking factor" in a
proteasome-dependent step.

PMID: 9030516 [PubMed - indexed for MEDLINE]


---------------------------------------------------------------