PMID- 12555062
OWN - NLM
STAT- MEDLINE
DCOM- 20030212
LR  - 20151119
IS  - 0950-9232 (Print)
IS  - 0950-9232 (Linking)
VI  - 22
IP  - 4
DP  - 2003 Jan 30
TI  - Paclitaxel induces inactivation of p70 S6 kinase and phosphorylation of Thr421 
      and Ser424 via multiple signaling pathways in mitosis.
PG  - 484-97
AB  - The 70 kDa ribosomal S6 kinase (p70S6K) is important for cell growth and 
      survival. Activation of p70S6K requires sequential phosphorylation of multiple 
      serine and threonine sites often triggered by growth factors and hormones. Here, 
      we report that paclitaxel, a microtubule-damaging agent, induces phosphorylation 
      of p70S6K at threonine 421 and serine 424 (T421/S424) in a concentration- and 
      time-dependent manner in multiple breast and ovarian cancer cell lines 
      demonstrated by a T421/S424 phospho-p70S6K antibody. Phosphoamino-acid analysis 
      and Western blot analysis by serine-/threonine-specific antibodies further 
      confirms that both serine and threonine residues are phosphorylated in p70S6K 
      following treatment with paclitaxel. Paclitaxel-induced p70S6K(T421/S424) 
      phosphorylation requires both de novo RNA and protein synthesis via multiple 
      signaling pathways including ERK1/2 MAP kinase, JNK, PKC, Ca(++), PI3K, and 
      mammalian target of rapamycin (mTOR). Despite phosphorylation of 
      p70S6K(T421/S424), paclitaxel inactivates this kinase in a concentration- and 
      time-dependent manner as illustrated by in vitro kinase assay. Inhibitors of 
      mTOR, PI3K, and Ca(++) impair p70S6K activity, whereas inhibitors of JNK and PKC 
      stimulate p70S6K activity. Inhibition of PKC and JNK prevents paclitaxel-induced 
      p70S6K inactivation. Moreover, the paclitaxel-induced phosphorylation and low 
      activity of p70S6K mainly occurs during mitosis. In summary, paclitaxel is able 
      to induce p70S6K(T421/S424) phosphorylation and decrease its activity in mitotic 
      cells via multiple signaling pathways. Our data suggest that paclitaxel-induced 
      p70S6K(T421/S424) phosphorylation and kinase inactivation are differentially 
      regulated. Our data also indicate that paclitaxel may exert its antitumor effect, 
      at least in part, via inhibition of p70S6K.
FAU - Le, Xiao-Feng
AU  - Le XF
AD  - Department of Experimental Therapeutics, The University of Texas MD Anderson 
      Cancer Center, Houston 77030, USA.
FAU - Hittelman, Walter N
AU  - Hittelman WN
FAU - Liu, Jiaxin
AU  - Liu J
FAU - McWatters, Amanda
AU  - McWatters A
FAU - Li, Chun
AU  - Li C
FAU - Mills, Gordon B
AU  - Mills GB
FAU - Bast, Robert C Jr
AU  - Bast RC Jr
LA  - eng
GR  - CA-39930/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - England
TA  - Oncogene
JT  - Oncogene
JID - 8711562
RN  - 0 (Antineoplastic Agents, Phytogenic)
RN  - 0 (Isoenzymes)
RN  - 2ZD004190S (Threonine)
RN  - 452VLY9402 (Serine)
RN  - EC 2.7.11.1 (Ribosomal Protein S6 Kinases)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinases)
RN  - EC 3.1.4.- (Type C Phospholipases)
RN  - EC 3.1.4.3 (Phospholipase C gamma)
RN  - P88XT4IS4D (Paclitaxel)
RN  - SY7Q814VUP (Calcium)
SB  - IM
MH  - Antineoplastic Agents, Phytogenic/*pharmacology
MH  - Blotting, Western
MH  - Calcium/metabolism
MH  - Humans
MH  - Isoenzymes/antagonists & inhibitors/metabolism
MH  - Mitogen-Activated Protein Kinases/antagonists & inhibitors
MH  - Mitosis/*drug effects
MH  - Paclitaxel/*pharmacology
MH  - Phospholipase C gamma
MH  - Phosphorylation
MH  - Precipitin Tests
MH  - Ribosomal Protein S6 Kinases/*antagonists & inhibitors
MH  - Serine/*metabolism
MH  - Signal Transduction/*drug effects
MH  - Threonine/*metabolism
MH  - Tumor Cells, Cultured
MH  - Type C Phospholipases/antagonists & inhibitors/metabolism
EDAT- 2003/01/30 04:00
MHDA- 2003/02/14 04:00
CRDT- 2003/01/30 04:00
PHST- 2003/01/30 04:00 [pubmed]
PHST- 2003/02/14 04:00 [medline]
PHST- 2003/01/30 04:00 [entrez]
AID - 1206175 [pii]
AID - 10.1038/sj.onc.1206175 [doi]
PST - ppublish
SO  - Oncogene. 2003 Jan 30;22(4):484-97. doi: 10.1038/sj.onc.1206175.