Cancer Cell. 2012 Feb 14;21(2):155-67.
170.02.12
‫הילה‬
An Animal Model of MYC-Driven Medulloblastoma.
Pei Y, Moore CE, Wang J, Tewari AK, Eroshkin A, Cho YJ, Witt H, Korshunov A, Read
TA, Sun JL, Schmitt EM, Miller CR, Buckley AF, McLendon RE, Westbrook TF,
Northcott PA, Taylor MD, Pfister SM, Febbo PG, Wechsler-Reya RJ.
Medulloblastoma (MB) is the most common malignant brain tumor in children. Patients
whose tumors exhibit overexpression or amplification of the MYC oncogene (c-MYC)
usually have an extremely poor prognosis, but there are no animal models of this subtype
of the disease. Here, we show that cerebellar stem cells expressing Myc and mutant
Trp53 (p53) generate aggressive tumors following orthotopic transplantation. These
tumors consist of large, pleiomorphic cells and resemble human MYC-driven MB at a
molecular level. Notably, antagonists of PI3K/mTOR signaling, but not Hedgehog
signaling, inhibit growth of tumor cells. These findings suggest that cerebellar stem cells
can give rise to MYC-driven MB and identify a novel model that can be used to test
therapies for this devastating disease.
PMID: 22340590
Cell. 2012 Jan 20;148(1-2):139-49.
17.02.012
‫יעקב‬
RNA dynamics in aging bacterial spores.
Segev E, Smith Y, Ben-Yehuda S.
Upon starvation, the bacterium Bacillus subtilis
enters the process of sporulation, lasting several hours and culminating in formation of a
spore, the most resilient cell type known. We show that a few days following sporulation,
the RNA profile of spores is highly dynamic. In aging spores incubated at high
temperatures, RNA content is globally decreased by degradation over several days. This
degradation might be a strategy utilized by the spore to facilitate its dormancy. However,
spores kept at low temperature exhibit a different RNA profile with evidence supporting
transcription. Further, we demonstrate that germination is affected by spore age,
incubation temperature, and RNA state, implying that spores can acquire dissimilar
characteristics at a time they are considered dormant. We propose that, in contrast to
current thinking, entering dormancy lasts a few days, during which spores are affected by
the environment and undergo corresponding molecular changes influencing their
emergence from quiescence.
PMID:22209493
Nature. 2012 Mar 18. doi: 10.1038/nature10914. [Epub ahead-print] 17.02.012 ‫יבגניה‬
MAP and kinesin-dependent nuclear positioning is required for skeletal muscle
function. Metzger T, Gache V, Xu M, Cadot B, Folker ES, Richardson BE, Gomes ER,
Baylies MK.
The basic unit of skeletal muscle in all metazoans is the multinucleate myofibre, within
which individual nuclei are regularly positioned. The molecular machinery responsible
for myonuclear positioning is not known. Improperly positioned nuclei are a hallmark of
numerous diseases of muscle, including centronuclear myopathies, but it is unclear
whether correct nuclear positioning is necessary for muscle function. Here we identify
the microtubule-associated protein ensconsin (Ens)/microtubule-associated protein 7
(MAP7) and kinesin heavy chain (Khc)/Kif5b as essential, evolutionarily conserved
regulators of myonuclear positioning in Drosophila and cultured mammalian myotubes.
We find that these proteins interact physically and that expression of the Kif5b motor
domain fused to the MAP7 microtubule-binding domain rescues nuclear positioning
defects in MAP7-depleted cells. This suggests that MAP7 links Kif5b to the microtubule
cytoskeleton to promote nuclear positioning. Finally, we show that myonuclear
positioning is physiologically important. Drosophila ens mutant larvae have decreased
locomotion and incorrect myonuclear positioning, and these phenotypes are rescued by
muscle-specific expression of Ens. We conclude that improper nuclear positioning
contributes to muscle dysfunction in a cell-autonomous fashion.
PMID:22425998
Cell. 2012 Feb 3;148(3):543-55.
22..02.12
‫שירן‬
PKCε promotes oncogenic functions of ATF2 in the nucleus while blocking its
apoptotic function at mitochondria.
Lau E, Kluger H, Varsano T, Lee K, Scheffler I, Rimm DL, Ideker T, Ronai ZA.
The transcription factor ATF2 elicits oncogenic activities in melanoma and tumor
suppressor activities in nonmalignant skin cancer. Here, we identify that ATF2 tumor
suppressor function is determined by its ability to localize at the mitochondria, where it
alters membrane permeability following genotoxic stress. The ability of ATF2 to reach
the mitochondria is determined by PKCε, which directs ATF2 nuclear localization.
Genotoxic stress attenuates PKCε effect on ATF2; enables ATF2 nuclear export and
localization at the mitochondria, where it perturbs the HK1-VDAC1 complex; increases
mitochondrial permeability; and promotes apoptosis. Significantly, high levels of PKCε,
as seen in melanoma cells, block ATF2 nuclear export and function at the mitochondria,
thereby attenuating apoptosis following exposure to genotoxic stress. In melanoma tumor
samples, high PKCε levels associate with poor prognosis. Overall, our findings provide
the framework for understanding how subcellular localization enables ATF2 oncogenic
or tumor suppressor functions.
PMID:22304920
Cell. 2012 Feb 17;148(4):716-26.???
22.5.2012
‫לינה‬
Mitochondrial Stress Engages E2F1 Apoptotic Signaling to Cause Deafness.
Raimundo N, Song L, Shutt TE, McKay SE, Cotney J, Guan MX, Gilliland TC, Hohuan
D, Santos-Sacchi J, Shadel GS.
Mitochondrial dysfunction causes poorly understood tissue-specific pathology stemming
from primary defects in respiration, coupled with altered reactive oxygen species (ROS),
metabolic signaling, and apoptosis. The A1555G mtDNA mutation that causes maternally
inherited deafness disrupts mitochondrial ribosome function, in part, via increased
methylation of the mitochondrial 12S rRNA by the methyltransferase mtTFB1. In patientderived A1555G cells, we show that 12S rRNA hypermethylation causes ROS-dependent
activation of AMP kinase and the proapoptotic nuclear transcription factor E2F1. This
retrograde mitochondrial-stress relay is operative in vivo, as transgenic-mtTFB1 mice exhibit
enhanced 12S rRNA methylation in multiple tissues, increased E2F1 and apoptosis in the
stria vascularis and spiral ganglion neurons of the inner ear, and progressive E2F1-dependent
hearing loss. This mouse mitochondrial disease model provides a robust platform for
deciphering the complex tissue specificity of human mitochondrial-based disorders, as well
as the precise pathogenic mechanism of maternally inherited deafness and its exacerbation by
environmental factors.
PMID:22341444