 |
 Previous Article | Next Article 
The Journal of Neuroscience, October 15, 1999, 19(20):8747-8756
Role of Cell Cycle Regulatory Proteins in Cerebellar Granule
Neuron Apoptosis
Jaya
Padmanabhan,
David S.
Park,
Lloyd A.
Greene, and
Michael L.
Shelanski
Department of Pathology and Center for Neurobiology and Behavior,
Taub Center for Alzheimer's Disease Research, College of Physicians
and Surgeons, Columbia University, New York, New York 10032
Cerebellar granule neurons (CGNs) undergo apoptosis when deprived
of depolarizing concentrations of KCl, but the underlying molecular
mechanisms are not yet clear. Although caspases have been postulated to
be involved in CGN cell death, inhibitors of caspases failed to prevent
apoptosis under our culture conditions, suggesting an involvement of
other molecules and pathways. We find that inhibitors of
cyclin-dependent kinases flavopiridol, olomoucine, and
roscovitineprotect CGNs from KCl withdrawal-induced apoptosis,
suggesting that cell cycle components play a significant role in the
death of these neurons. Analysis of the different cell cycle regulatory
elements in this model revealed that apoptosis is preceded by an
increase in the level of cyclin E protein, with elevated nuclear levels
of cyclin D1 and with enhanced activity of the cyclin D1- and E-
associated kinases. In addition, there was a significant decrease in
the level of the cyclin-dependent kinase (cdk) inhibitor p27. In
agreement with these changes, analysis of a major substrate of
cyclin-activated cdks, retinoblastoma protein (Rb), showed an increase
in the level of phosphorylated forms within 1 hr of KCl withdrawal.
Moreover, the overall levels of Rb protein were significantly reduced
within 6-12 hr of KCl withdrawal and did so by a caspase-independent
mechanism. All of these responses were blocked by cdk inhibitors. These
findings indicate that cdks act at an early step in the pathway by
which KCl withdrawal induces apoptotic death of cerebellar granule
cells and suggest that additional elements of the cell cycle machinery participate in this mechanism.
Key words:
neurons; apoptosis; cell cycle; cyclins; cdk; Rb; CKI
Copyright © 1999 Society for Neuroscience 0270-6474/99/19208747-10$05.00/0
This article has been cited by other articles:
|
|
|
|
 
Z. Yuan, M. K. Lehtinen, P. Merlo, J. Villen, S. Gygi, and A. Bonni
Regulation of Neuronal Cell Death by MST1-FOXO1 Signaling
J. Biol. Chem.,
April 24, 2009;
284(17):
11285 - 11292.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
X. Li, X. Tang, B. Jablonska, A. Aguirre, V. Gallo, and M. B. Luskin
p27KIP1 Regulates Neurogenesis in the Rostral Migratory Stream and Olfactory Bulb of the Postnatal Mouse
J. Neurosci.,
March 4, 2009;
29(9):
2902 - 2914.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. R. Gonzalez, Y. Zhang, D. Behzadpoor, S. Cregan, S. Bamforth, R. S. Slack, and D. S. Park
CITED2 Signals through Peroxisome Proliferator-Activated Receptor-{gamma} to Regulate Death of Cortical Neurons after DNA Damage
J. Neurosci.,
May 21, 2008;
28(21):
5559 - 5569.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Akashiba, Y. Ikegaya, N. Nishiyama, and N. Matsuki
Differential Involvement of Cell Cycle Reactivation between Striatal and Cortical Neurons in Cell Death Induced by 3-Nitropropionic Acid
J. Biol. Chem.,
March 7, 2008;
283(10):
6594 - 6606.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. M. Wright, M. I. Smith, L. Farrag, and M. Deshmukh
Chromatin modification of Apaf-1 restricts the apoptotic pathway in mature neurons
J. Cell Biol.,
December 3, 2007;
179(5):
825 - 832.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Kurita, T. Kuwajima, I. Nishimura, and K. Yoshikawa
Necdin Downregulates Cdc2 Expression to Attenuate Neuronal Apoptosis.
J. Neurosci.,
November 15, 2006;
26(46):
12003 - 12013.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. Zhang, D. Qu, E. J. Morris, M. J. O'Hare, S. M. Callaghan, R. S. Slack, H. M. Geller, and D. S. Park
The Chk1/Cdc25A Pathway as Activators of the Cell Cycle in Neuronal Death Induced by Camptothecin.
J. Neurosci.,
August 23, 2006;
26(34):
8819 - 8828.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Naetzker, N. Hagen, and G. van Echten-Deckert
Activation of p38 mitogen-activated protein kinase and partial reactivation of the cell cycle by cis-4-methylsphingosine direct postmitotic neurons towards apoptosis
Genes Cells,
March 1, 2006;
11(3):
269 - 279.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. J. O'Hare, N. Kushwaha, Y. Zhang, H. Aleyasin, S. M. Callaghan, R. S. Slack, P. R. Albert, I. Vincent, and D. S. Park
Differential Roles of Nuclear and Cytoplasmic Cyclin-Dependent Kinase 5 in Apoptotic and Excitotoxic Neuronal Death
J. Neurosci.,
September 28, 2005;
25(39):
8954 - 8966.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. C. Biswas, D. X. Liu, and L. A. Greene
Bim Is a Direct Target of a Neuronal E2F-Dependent Apoptotic Pathway
J. Neurosci.,
September 14, 2005;
25(37):
8349 - 8358.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Di Giovanni, V. Movsesyan, F. Ahmed, I. Cernak, S. Schinelli, B. Stoica, and A. I. Faden
Cell cycle inhibition provides neuroprotection and reduces glial proliferation and scar formation after traumatic brain injury
PNAS,
June 7, 2005;
102(23):
8333 - 8338.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. X. Liu, N. Nath, S. P. Chellappan, and L. A. Greene
Regulation of neuron survival and death by p130 and associated chromatin modifiers
Genes & Dev.,
March 15, 2005;
19(6):
719 - 732.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. B. Benedito, M. Lehtinen, R. Massol, U. G. Lopes, T. Kirchhausen, A. Rao, and A. Bonni
The Transcription Factor NFAT3 Mediates Neuronal Survival
J. Biol. Chem.,
January 28, 2005;
280(4):
2818 - 2825.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Perez-Gomez, A. Garcia-Rodriguez, K. J. James, A. Ferrero-Gutierrez, A. Novelli, and M. T. Fernandez-Sanchez
The Marine Toxin Dinophysistoxin-2 Induces Differential Apoptotic Death of Rat Cerebellar Neurons and Astrocytes
Toxicol. Sci.,
July 1, 2004;
80(1):
74 - 82.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. M. Price, R. L. Safirstein, and J. Megyesi
Protection of renal cells from cisplatin toxicity by cell cycle inhibitors
Am J Physiol Renal Physiol,
February 1, 2004;
286(2):
F378 - F384.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. Maejima, S. Adachi, H. Ito, K. Nobori, M. Tamamori-Adachi, and M. Isobe
Nitric oxide inhibits ischemia/reperfusion-induced myocardial apoptosis by modulating cyclin A-associated kinase activity
Cardiovasc Res,
August 1, 2003;
59(2):
308 - 320.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. G. Besirli and E. M. Johnson Jr.
JNK-independent Activation of c-Jun during Neuronal Apoptosis Induced by Multiple DNA-damaging Agents
J. Biol. Chem.,
June 13, 2003;
278(25):
22357 - 22366.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Subramaniam, J. Strelau, and K. Unsicker
Growth Differentiation Factor-15 Prevents Low Potassium-induced Cell Death of Cerebellar Granule Neurons by Differential Regulation of Akt and ERK Pathways
J. Biol. Chem.,
March 7, 2003;
278(11):
8904 - 8912.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. Konishi and A. Bonni
The E2F-Cdc2 Cell-Cycle Pathway Specifically Mediates Activity Deprivation-Induced Apoptosis of Postmitotic Neurons
J. Neurosci.,
March 1, 2003;
23(5):
1649 - 1658.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Ranganathan and R. Bowser
Alterations in G1 to S Phase Cell-Cycle Regulators during Amyotrophic Lateral Sclerosis
Am. J. Pathol.,
March 1, 2003;
162(3):
823 - 835.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. J. Rideout, Q. Wang, D. S. Park, and L. Stefanis
Cyclin-Dependent Kinase Activity Is Required for Apoptotic Death But Not Inclusion Formation in Cortical Neurons after Proteasomal Inhibition
J. Neurosci.,
February 15, 2003;
23(4):
1237 - 1245.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. M. Schang
Cyclin-dependent kinases as cellular targets for antiviral drugs
J. Antimicrob. Chemother.,
December 1, 2002;
50(6):
779 - 792.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. Gaudilliere, Y. Shi, and A. Bonni
RNA Interference Reveals a Requirement for Myocyte Enhancer Factor 2A in Activity-dependent Neuronal Survival
J. Biol. Chem.,
November 22, 2002;
277(48):
46442 - 46446.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. H. Ghahremani, E. Keramaris, T. Shree, Z. Xia, R. J. Davis, R. Flavell, R. S. Slack, and D. S. Park
Interaction of the c-Jun/JNK Pathway and Cyclin-dependent Kinases in Death of Embryonic Cortical Neurons Evoked by DNA Damage
J. Biol. Chem.,
September 13, 2002;
277(38):
35586 - 35596.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. M. Schang, A. Bantly, and P. A. Schaffer
Explant-Induced Reactivation of Herpes Simplex Virus Occurs in Neurons Expressing Nuclear cdk2 and cdk4
J. Virol.,
June 27, 2002;
76(15):
7724 - 7735.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. RIMONDINI, C. ARLINDE, W. SOMMER, and M. HEILIG
Long-lasting increase in voluntary ethanol consumption and transcriptional regulation in the rat brain after intermittent exposure to alcohol
FASEB J,
January 1, 2002;
16(1):
27 - 35.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. M. Duplan, Y. Theoret, and R. Kenigsberg
Antitumor Activity of Fibroblast Growth Factors (FGFs) for Medulloblastoma May Correlate with FGF Receptor Expression and Tumor Variant
Clin. Cancer Res.,
January 1, 2002;
8(1):
246 - 257.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. V. Velentza, A. M. Schumacher, C. Weiss, M. Egli, and D. M. Watterson
A Protein Kinase Associated with Apoptosis and Tumor Suppression. STRUCTURE, ACTIVITY, AND DISCOVERY OF PEPTIDE SUBSTRATES
J. Biol. Chem.,
October 12, 2001;
276(42):
38956 - 38965.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Katchanov, C. Harms, K. Gertz, L. Hauck, C. Waeber, L. Hirt, J. Priller, R. von Harsdorf, W. Bruck, H. Hortnagl, et al.
Mild Cerebral Ischemia Induces Loss of Cyclin-Dependent Kinase Inhibitors and Activation of Cell Cycle Machinery before Delayed Neuronal Cell Death
J. Neurosci.,
July 15, 2001;
21(14):
5045 - 5053.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Adachi, H. Ito, M. Tamamori-Adachi, Y. Ono, T. Nozato, S. Abe, M.-a. Ikeda, F. Marumo, and M. Hiroe
Cyclin A/cdk2 Activation Is Involved in Hypoxia-Induced Apoptosis in Cardiomyocytes
Circ. Res.,
March 2, 2001;
88(4):
408 - 414.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Miki, K. Kadota, H. Bono, Y. Mizuno, Y. Tomaru, P. Carninci, M. Itoh, K. Shibata, J. Kawai, H. Konno, et al.
Delineating developmental and metabolic pathways in vivo by expression profiling using the RIKEN set of 18,816 full-length enriched mouse cDNA arrays
PNAS,
February 27, 2001;
98(5):
2199 - 2204.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Osuga, S. Osuga, F. Wang, R. Fetni, M. J. Hogan, R. S. Slack, A. M. Hakim, J.-E Ikeda, and D. S. Park
Cyclin-dependent kinases as a therapeutic target for stroke
PNAS,
August 10, 2000;
(2000)
170144197.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
H. Nadeau, S. McKinney, D. J. Anderson, and H. A. Lester
ROMK1 (Kir1.1) Causes Apoptosis and Chronic Silencing of Hippocampal Neurons
J Neurophysiol,
August 1, 2000;
84(2):
1062 - 1075.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. S. Park, E. J. Morris, R. Bremner, E. Keramaris, J. Padmanabhan, M. Rosenbaum, M. L. Shelanski, H. M. Geller, and L. A. Greene
Involvement of Retinoblastoma Family Members and E2F/DP Complexes in the Death of Neurons Evoked by DNA Damage
J. Neurosci.,
May 1, 2000;
20(9):
3104 - 3114.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. J. O'Hare, S. T. Hou, E. J. Morris, S. P. Cregan, Q. Xu, R. S. Slack, and D. S. Park
Induction and Modulation of Cerebellar Granule Neuron Death by E2F-1
J. Biol. Chem.,
August 11, 2000;
275(33):
25358 - 25364.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Osuga, S. Osuga, F. Wang, R. Fetni, M. J. Hogan, R. S. Slack, A. M. Hakim, J.-E Ikeda, and D. S. Park
Cyclin-dependent kinases as a therapeutic target for stroke
PNAS,
August 29, 2000;
97(18):
10254 - 10259.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
