Cancer:
Cervical
Colon
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Parkinson,s Disease
Smocking
Stem cell
2010/5/11
Cell Stem Cell. 2010 Nov 5;7(5):606-17. Abbas
HA, Maccio
DR, Coskun
S, Jackson
JG, Hazen
AL, Sills
TM, You
MJ, Hirschi
KK, Lozano
G. Program in Genes and
Development of The Graduate School of Biomedical Sciences, University of
Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Mdm2 is an E3 ubiquitin ligase
that targets p53 for degradation. p53(515C) (encoding p53R172P) is a
hypomorphic allele of p53 that rescues the embryonic lethality of Mdm2(-/-)
mice. Mdm2(-/-) p53(515C/515C) mice, however, die by postnatal day 13
resulting from hematopoietic failure. Hematopoietic stem cells and
progenitors of Mdm2(-/-) p53(515C/515C) mice were normal in fetal livers
but were depleted in postnatal bone marrows. After birth, these mice had
elevated reactive oxygen species (ROS) thus activating p53R172P. In the
absence of Mdm2, stable p53R172P induced ROS and cell cycle arrest, senescence,
and cell death in the hematopoietic compartment. This phenotype was
partially rescued with antioxidant treatment and upon culturing of
hematopoietic cells in methycellulose at 3% oxygen. p16 was also stabilized
because of ROS, and its loss increased cell cycling and partially rescued
hematopoiesis and survival. Thus, Mdm2 is required to control ROS-induced
p53 levels for sustainable hematopoiesis. Copyright © 2010 Elsevier Inc. All rights reserved. J Immunol. 1995
Apr 15;154(8):3732-41. Jacobsen FW, Dubois CM, Rusten LS, Veiby OP, Jacobsen SE. Department of Immunology,
Norwegian Radium Hospital, Oslo. TNF-alpha is a pleiotropic
cytokine with stimulatory as well as inhibitory effects on hematopoiesis.
We have previously demonstrated that TNF-alpha directly inhibits
CSF-induced proliferation of primitive murine lineage-negative bone marrow
progenitors (Lin-) and stem cell antigen-1 hematopoietic progenitors
through the 75-kDa TNF receptor (TNF-R2), whereas TNF-alpha-induced
inhibition of more committed Lin- progenitors is mediated through the
55-kDa TNF-R (TNF-R1), indicating a differential role of the two TNF-Rs in
hematopoiesis. Numerous studies have demonstrated the ability of stem cell
factor (SCF), a key regulator of hematopoiesis signaling through c-kit, to
synergize with other hematopoietic growth factors, but little is known
about cytokines capable of inhibiting hematopoiesis induced by SCF. While
TNF-alpha has been demonstrated to enhance SCF-induced proliferation of
myeloid leukemia blasts, the present report demonstrates that TNF-alpha, by
signaling through TNF-R2, inhibits SCF-induced proliferation of normal
murine Lin- and stem cell antigen-1 hematopoietic progenitors.
SCF-stimulated proliferation of the hematopoietic cell line FDC-P1 was also
potently inhibited by TNF-alpha and was accompanied by down-regulation of
c-kit cell surface expression as well as c-kit mRNA levels. Finally,
treatment of the FDC-P1 cell line with TNF-alpha resulted in increased
levels of the tumor suppressor p53 mRNA, suggesting another mechanism by
which hematopoietic effects of TNF-alpha may be mediated. PMID:
7535812 [PubMed - indexed Cancer Cell. 2002 Jun;1(5):493-503. Tergaonkar V, Pando M, Vafa O, Wahl G, Verma I. Laboratory of Genetics, The
Salk Institute for Biological Studies, La Jolla, California 92037, USA. Chemotherapeutic agents
simultaneously induce transcription factors p53 and NFkappaB. p53 induction
can activate an apoptotic program, and resistance to chemotherapy
correlates with the loss of a functional p53 pathway. By contrast, NFkappaB
prevents apoptosis in response to chemotherapeutic agents. We have analyzed
the p53 response in IKK1/2(-/-) MEFs, which lack detectable NFkappaB
activity. Compared to WT fibroblasts, IKK1/2(-/-) fibroblasts showed
increased cell death and p53 induction in response to the chemotherapeutic
agent, doxorubicin. Reconstitution of IKK2, but not IKK1, increased Mdm2
levels and decreased doxorubicin-induced p53 stabilization and cell death.
IKK2-mediated effects required its kinase function and were abrogated by
coexpression of the dominant negative IkappaBalphaM, implying a role for
NFkappaB in blocking chemotherapy-induced p53 and cell death. PMID:
12124178 [PubMed - indexed for MEDLINE] Proc Natl Acad Sci U S A. 2009 Feb
24;106(8):2629-34. Epub 2009 Feb 5. Xia Y, Padre RC, De Mendoza TH, Bottero V, Tergaonkar VB, Verma IM. Laboratory of Genetics, The
Salk Institute for Biological Studies, La Jolla, CA 92037, USA. Functional inactivation of
p53 and constitutive activation of the NF-kappaB pathway has been
associated with several human cancers. In this study, we show that IkappaB
kinase 2 (IKK2/IKKbeta), which is critical for NF-kappaB activation, also
phosphorylates p53. Phosphorylation of p53 at serines 362 and 366 by IKK2
leads to its recruitment to and ubiquitination by beta-TrCP1. Degradation
of ubiquitinated p53 is independent of Mdm2, because it occurs in both
wild-type and Mdm2(-/-) cells. SiRNA-mediated reduction in the levels of
beta-TrCP1 and other members of the SCF(beta-TrCP1)E3 ubiquitin ligase
complex or overexpression of a dominant negative form of beta-TrCP1
enhances p53 stability. Substitutions at Ser-362 and 366 of p53 by alanines
(p53 AA) result in reduced phosphorylation of p53 by IKK2, decreased
association with beta-TrCP1, and thus increased stability of p53 and
expression of p53 target genes such as p21, altering the G1 phase of the
cell cycle. Our results identify IKK2 and beta-TrCP1 as novel regulators of
the p53 pathway and suggest that blocking of IKK2 and beta-TrCP1 could be a
means of regulating p53 stability and thereby modulating its biological
activity. PMID:
19196987 [PubMed - indexed Cancer Lett. 2008 Sep 8;268(1):137-45. Epub
2008 May 22. Department of Medicine,
Veterans Healthcare Medical Center, San Diego, CA 92161, USA.
mbuck@ucsd.edu The interactions between
BRCA1 and p53 are relevant for understanding hereditary breast and ovarian
cancer. Although in vitro studies reported that BRCA1 (amino acids 224-500)
and the second BRCT domain of the BRCA1 C-terminus may interact with p53,
quantitative biophysical measurements indicate that these regions of BRCA1
do not bind efficiently to p53. Here we show that BRCA1 interacts with p53
in vivo in breast cancer cells, through another BRCA1 domain (amino acids
772-1292). Expression of a truncated BRCA1 (amino acids 772-1292)
stimulated p53 DNA-binding and transcription activities and apoptosis,
recapitulating some effects of DNA damage. These results suggest that a
novel domain of BRCA1 may interact with p53 in breast cancer cells. PMID:
18501503 [PubMed - indexed for MEDLINE]
Mdm2 is required for survival of hematopoietic stem cells/progenitors
via dampening of ROS-induced p53 activity.
Abstract
Inhibition of stem cell
factor-induced proliferation of primitive murine hematopoietic progenitor
cells signaled through the 75-kilodalton tumor necrosis factor receptor.
Regulation of c-kit and p53 expression.
Abstract
p53 stabilization is
decreased upon NFkappaB activation: a role for NFkappaB in acquisition of
resistance to chemotherapy.
Abstract
Phosphorylation of p53 by
IkappaB kinase 2 promotes its degradation by beta-TrCP.
Abstract
A novel domain of BRCA1
interacts with p53 in breast cancer cells.
Abstract