PMID- 10567572
OWN - NLM
STAT- MEDLINE
DCOM- 20000106
LR  - 20190508
IS  - 0270-7306 (Print)
IS  - 0270-7306 (Linking)
VI  - 19
IP  - 12
DP  - 1999 Dec
TI  - BCL-2 is phosphorylated and inactivated by an ASK1/Jun N-terminal protein kinase 
      pathway normally activated at G(2)/M.
PG  - 8469-78
AB  - Multiple signal transduction pathways are capable of modifying BCL-2 family
      members to reset susceptibility to apoptosis. We used two-dimensional peptide
      mapping and sequencing to identify three residues (Ser70, Ser87, and Thr69)
      within the unstructured loop of BCL-2 that were phosphorylated in response to
      microtubule-damaging agents, which also arrest cells at G(2)/M. Changing these
      sites to alanine conferred more antiapoptotic activity on BCL-2 following
      physiologic death signals as well as paclitaxel, indicating that phosphorylation 
      is inactivating. An examination of cycling cells enriched by elutriation for
      distinct phases of the cell cycle revealed that BCL-2 was phosphorylated at the
      G(2)/M phase of the cell cycle. G(2)/M-phase cells proved more susceptible to
      death signals, and phosphorylation of BCL-2 appeared to be responsible, as a
      Ser70Ala substitution restored resistance to apoptosis. We noted that ASK1 and
      JNK1 were normally activated at G(2)/M phase, and JNK was capable of
      phosphorylating BCL-2. Expression of a series of wild-type and dominant-negative 
      kinases indicated an ASK1/Jun N-terminal protein kinase 1 (JNK1) pathway
      phosphorylated BCL-2 in vivo. Moreover, the combination of dominant negative
      ASK1, (dnASK1), dnMKK7, and dnJNK1 inhibited paclitaxel-induced BCL-2
      phosphorylation. Thus, stress response kinases phosphorylate BCL-2 during cell
      cycle progression as a normal physiologic process to inactivate BCL-2 at G(2)/M.
FAU - Yamamoto, K
AU  - Yamamoto K
AD  - Departments of Pathology and Medicine, Harvard Medical School and Dana-Farber
      Cancer Institute, Boston, Massachusetts 02115, USA.
FAU - Ichijo, H
AU  - Ichijo H
FAU - Korsmeyer, S J
AU  - Korsmeyer SJ
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Mol Cell Biol
JT  - Molecular and cellular biology
JID - 8109087
RN  - 0 (CCNB1 protein, human)
RN  - 0 (Cyclin B)
RN  - 0 (Cyclin B1)
RN  - 0 (Proto-Oncogene Proteins c-bcl-2)
RN  - 2ZD004190S (Threonine)
RN  - 452VLY9402 (Serine)
RN  - EC 2.7.11.22 (CDC2 Protein Kinase)
RN  - EC 2.7.11.24 (JNK Mitogen-Activated Protein Kinases)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinases)
RN  - EC 2.7.11.25 (MAP Kinase Kinase Kinase 5)
RN  - EC 2.7.11.25 (MAP Kinase Kinase Kinases)
RN  - EC 2.7.11.25 (MAP3K5 protein, human)
RN  - EC 2.7.12.2 (MAP Kinase Kinase 7)
RN  - EC 2.7.12.2 (MAP2K7 protein, human)
RN  - EC 2.7.12.2 (Mitogen-Activated Protein Kinase Kinases)
RN  - P88XT4IS4D (Paclitaxel)
SB  - IM
MH  - Amino Acid Sequence
MH  - Apoptosis
MH  - Binding Sites
MH  - CDC2 Protein Kinase/metabolism
MH  - Cyclin B/metabolism
MH  - Cyclin B1
MH  - Enzyme Activation
MH  - G2 Phase
MH  - Humans
MH  - JNK Mitogen-Activated Protein Kinases
MH  - Jurkat Cells
MH  - MAP Kinase Kinase 7
MH  - MAP Kinase Kinase Kinase 5
MH  - MAP Kinase Kinase Kinases/*metabolism
MH  - *MAP Kinase Signaling System
MH  - Microtubules/drug effects
MH  - Mitogen-Activated Protein Kinase Kinases/metabolism
MH  - Mitogen-Activated Protein Kinases/*metabolism
MH  - Mitosis
MH  - Molecular Sequence Data
MH  - Mutagenesis
MH  - Paclitaxel/pharmacology
MH  - Phosphorylation
MH  - Proto-Oncogene Proteins c-bcl-2/genetics/*metabolism
MH  - Serine/genetics/metabolism
MH  - Threonine/genetics/metabolism
PMC - PMC84954
EDAT- 1999/11/24 00:00
MHDA- 1999/11/24 00:01
CRDT- 1999/11/24 00:00
PHST- 1999/11/24 00:00 [pubmed]
PHST- 1999/11/24 00:01 [medline]
PHST- 1999/11/24 00:00 [entrez]
AID - 10.1128/mcb.19.12.8469 [doi]
PST - ppublish
SO  - Mol Cell Biol. 1999 Dec;19(12):8469-78. doi: 10.1128/mcb.19.12.8469.