Table of Contents
1
UI - 11731874
AU - Di Donato S; Gellera C; Mariotti C
TI -
The complex clinical and genetic classification of inherited ataxias.
II. Autosomal recessive ataxias.
SO - Neurol Sci 2001 Jun;22(3):219-28
AD - Division of Biochemistry and Genetics, C. Besta National Neurological
Institute, Via Celoria 11, I-20133 Milan, Italy.
Autosomal recessive ataxias are a heterogeneous group of rare
neurodegenerative diseases characterized by early onset cerebellar
ataxia associated with various neurologic, ophthalmologic and systemic
signs. In comparison with autosomal dominant ataxias, the group of
recessive ataxias is less extensively characterized. In fact, only a few
conditions have been genetically characterized. The pathogenesis of
these forms is associated with a "loss of function" of specific cellular
proteins involved in metabolic homeostasis, cell cycle, and DNA
repair/protection processing. The two most common autosomal recessive
ataxias, in European countries, are Friedreich's ataxia and ataxia
telangiectasia. Other forms are much less frequent, and include ataxia
with vitamin E deficiency, abetalipoproteinemia. Refsum's disease,
spastic ataxia, infantile onset spinocerebellar ataxia, and ataxia with
oculomotor apraxia. These pathological conditions, although extremely
rare, have nevertheless to be carefully considered in differential
diagnosis, not only for correct nosographical classification, but
particularly, for specific prognostic and therapeutic implications. Some
of these diseases exhibit a peculiar regional distribution. An updated
review of the clinical, genetic, and pathogenic aspects of recessive
ataxias is presented. Specific management problems with respect to
diagnosis and genetic counseling are discussed.
2
UI - 11821961
AU - Bradshaw PS; Condie A; Matutes E; Catovsky D; Yuille MR
TI -
Breakpoints in the ataxia telangiectasia gene arise at the RGYW somatic
hypermutation motif.
SO - Oncogene 2002 Jan 17;21(3):483-7
AD - Academic Department of Haematology and Cytogenetics, Institute of Cancer
Research, Sutton, Surrey, UK.
The mature sporadic T-cell malignancy, T-cell prolymphocytic leukemia
(T-PLL) is remarkable for frequently harbouring somatic mutations of the
Ataxia Telangiectasia (A-T) gene, ATM. Because some data suggest ATM is
frequently rearranged in T-PLL, it was decided to investigate such
rearrangements in detail by cloning breakpoints. Among 17 T-PLL tumour
samples, three rearrangements were detected by Southern blotting. Two
cases harboured a unique type of intragenic duplication in which
breakpoints arose at the consensus sequence RGYW/WRCY. The third case
harboured a large deletion terminating within the ATM gene. Also, 13
T-cell acute lymphoblastic leukemia (T-ALL) samples were examined and
one sample harboured a deletion- insertion with the RGYW motif at the
breakpoint in ATM. This is the first known deleterious mutation detected
in ATM in T-ALL. Interestingly, the RGYW motif is the signal for a
cell-cycle regulated DNA double strand break (DSB) that initiates
somatic hypermutation of immunoglobulin and, probably, T-cell receptor
genes. The structures of the ATM duplications suggest they may arise
from an error in somatic hypermutation. We suggest that aberrant
components of somatic hypermutation may contribute to the defective DSB
repair characteristic of cancer.
3
UI - 11741320
AU - Theard D; Coisy M; Ducommun B; Concannon P; Darbon JM
TI -
Etoposide and adriamycin but not genistein can activate the checkpoint
kinase Chk2 independently of ATM/ATR.
SO - Biochem Biophys Res Commun 2001 Dec 21;289(5):1199-204
AD - Laboratoire de Biologie Cellulaire et Moleculaire du Controle de la
Proliferation, UMR 5088 CNRS, Universite Paul Sabatier, Bat 4R3B1, 118
route de Narbonne, Toulouse, 31062, France.
We have investigated the effects of three unrelated topoisomerase 2
inhibitors, genistein, adriamycin, and etoposide, on
phosphorylation/activation of the checkpoint kinase Chk2 in normal or
ATM-deficient (ATM-) human fibroblasts and in cells overexpressing a
catalytically inactive ATR kinase. We demonstrate that genistein
activates Chk2 in a strictly ATM-dependent manner, whereas etoposide and
adriamycin can trigger Chk2 activation in long-term cultures of ATM-
cells. Moreover, these two latter genotoxic compounds were found to
activate Chk2 in fibroblasts expressing the dominant negative form of
ATR. We also report a significant decrease in the accumulation in
G2-phase of ATM- cells when genistein did not activate Chk2. In
conclusion, our results strongly support that activation of Chk2 could
be dependent on the type and/or extent of DNA damage and under the
control of either an ATM-dependent or an ATM and, maybe, an
ATR-independent pathway.
4
UI - 10454555
AU - Smith GC; d'Adda di Fagagna F; Lakin ND; Jackson SP
TI -
Cleavage and inactivation of ATM during apoptosis.
SO - Mol Cell Biol 1999 Sep;19(9):6076-84
AD - Wellcome/CRC Institute and Department of Zoology, University of
Cambridge, Cambridge, United Kingdom.
The activation of the cysteine proteases with aspartate specificity,
termed caspases, is of fundamental importance for the execution of
programmed cell death. These proteases are highly specific in their
action and activate or inhibit a variety of key protein molecules in the
cell. Here, we study the effect of apoptosis on the integrity of two
proteins that have critical roles in DNA damage signalling, cell cycle
checkpoint controls, and genome maintenance-the product of the gene
defective in ataxia telangiectasia, ATM, and the related protein ATR. We
find that ATM but not ATR is specifically cleaved in cells induced to
undergo apoptosis by a variety of stimuli. We establish that ATM
cleavage in vivo is dependent on caspases, reveal that ATM is an
efficient substrate for caspase 3 but not caspase 6 in vitro, and show
that the in vitro caspase 3 cleavage pattern mirrors that in cells
undergoing apoptosis. Strikingly, apoptotic cleavage of ATM in vivo
abrogates its protein kinase activity against p53 but has no apparent
effect on the DNA binding properties of ATM. These data suggest that the
cleavage of ATM during apoptosis generates a kinase-inactive protein
that acts, through its DNA binding ability, in a trans-dominant-negative
fashion to prevent DNA repair and DNA damage signalling.
5
UI - 11587230
AU - Viniou N; Terpos E; Rombos J; Vaiopoulos G; Nodaros K; Stamatopoulos K;
TI -
Meletis J; Yataganas X
Acute myeloid leukemia in a patient with ataxia-telangiectasia: a case
report and review of the literature.
SO - Leukemia 2001 Oct;15(10):1668-70
6
UI - 11850813
AU - Bar-Shira A; Rashi-Elkeles S; Zlochover L; Moyal L; Smorodinsky NI;
TI -
Seger R; Shiloh Y
ATM-dependent activation of the gene encoding MAP kinase phosphatase 5
by radiomimetic DNA damage.
SO - Oncogene 2002 Jan 24;21(5):849-55
AD - The David and Inez Myers Laboratory for Genetic Research, Department of
Human Genetics and Molecular Medicine, Sackler School of Medicine, Tel
Aviv University, Tel Aviv 69978, Israel.
Cellular responses to DNA damage are mediated by an extensive network of
signaling pathways. The ATM protein kinase is a master regulator of the
response to double-strand breaks (DSBs), the most cytotoxic DNA lesion
caused by ionizing radiation. ATM is the protein missing or inactive in
patients with the pleiotropic genetic disorder ataxia-telangiectasia
(A-T). A major response to DNA damage is altered expression of numerous
genes. While studying gene expression in control and A-T cells following
treatment with the radiomimetic chemical neocarzinostatin (NCS), we
identified an expressed sequence tag that represented a gene that was
induced by DSBs in an ATM-dependent manner. The corresponding cDNA
encoded a dual specificity phosphatase of the MAP kinase phosphatase
family, MKP-5. MKP-5 dephosphorylates and inactivates the
stress-activated MAP kinases JNK and p38. The
phosphorylation-dephosphorylation cycle of JNK and p38 by NCS was
attenuated in A-T cells. Thus, ATM modulates this cycle in response to
DSBs. These results further highlight ATM as a link between the DNA
damage response and major signaling pathways involved in proliferative
and apoptotic processes.
7
UI - 11809797
AU - Xu B; Kim ST; Lim DS; Kastan MB
TI -
Two molecularly distinct G(2)/M checkpoints are induced by ionizing
irradiation.
SO - Mol Cell Biol 2002 Feb;22(4):1049-59
AD - Department of Hematology-Oncology, St. Jude Children's Research
Hospital, Memphis, Tennessee 38105, USA.
Cell cycle checkpoints are among the multiple mechanisms that eukaryotic
cells possess to maintain genomic integrity and minimize tumorigenesis.
Ionizing irradiation (IR) induces measurable arrests in the G(1), S, and
G(2) phases of the mammalian cell cycle, and the ATM (ataxia
telangiectasia mutated) protein plays a role in initiating checkpoint
pathways in all three of these cell cycle phases. However, cells lacking
ATM function exhibit both a defective G(2) checkpoint and a prolonged
G(2) arrest after IR, suggesting the existence of different types of
G(2) arrest. Two molecularly distinct G(2)/M checkpoints were
identified, and the critical importance of the choice of G(2)/M
checkpoint assay was demonstrated. The first of these G(2)/M checkpoints
occurs early after IR, is very transient, is ATM dependent and dose
independent (between 1 and 10 Gy), and represents the failure of cells
which had been in G(2) at the time of irradiation to progress into
mitosis. Cell cycle assays that can distinguish mitotic cells from G(2)
cells must be used to assess this arrest. In contrast, G(2)/M
accumulation, typically assessed by propidium iodide staining, begins to
be measurable only several hours after IR, is ATM independent, is dose
dependent, and represents the accumulation of cells that had been in
earlier phases of the cell cycle at the time of exposure to radiation.
G(2)/M accumulation after IR is not affected by the early G(2)/M
checkpoint and is enhanced in cells lacking the IR-induced S-phase
checkpoint, such as those lacking Nbs1 or Brca1 function, because of a
prolonged G(2) arrest of cells that had been in S phase at the time of
irradiation. Finally, neither the S-phase checkpoint nor the G(2)
checkpoints appear to affect survival following irradiation. Thus, two
different G(2) arrest mechanisms are present in mammalian cells, and the
type of cell cycle checkpoint assay to be used in experimental
investigation must be thoughtfully selected.
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