PMID- 10579725
OWN - NLM
STAT- MEDLINE
DCOM- 19991230
LR  - 20191023
IS  - 0021-9525 (Print)
IS  - 0021-9525 (Linking)
VI  - 147
IP  - 5
DP  - 1999 Nov 29
TI  - p53 inhibits alpha 6 beta 4 integrin survival signaling by promoting the caspase 
      3-dependent cleavage of AKT/PKB.
PG  - 1063-72
AB  - Although the interaction of matrix proteins with integrins is known to initiate
      signaling pathways that are essential for cell survival, a role for tumor
      suppressors in the regulation of these pathways has not been established. We
      demonstrate here that p53 can inhibit the survival function of integrins by
      inducing the caspase-dependent cleavage and inactivation of the serine/threonine 
      kinase AKT/PKB. Specifically, we show that the alpha6beta4 integrin promotes the 
      survival of p53-deficient carcinoma cells by activating AKT/PKB. In contrast,
      this integrin does not activate AKT/PKB in carcinoma cells that express wild-type
      p53 and it actually stimulates their apoptosis, in agreement with our previous
      findings (Bachelder, R.E., A. Marchetti, R. Falcioni, S. Soddu, and A.M.
      Mercurio. 1999. J. Biol. Chem. 274:20733-20737). Interestingly, we observed
      reduced levels of AKT/PKB protein after antibody clustering of alpha6beta4 in
      carcinoma cells that express wild-type p53. In contrast, alpha6beta4 clustering
      did not reduce the level of AKT/PKB in carcinoma cells that lack functional p53. 
      The involvement of caspase 3 in AKT/PKB regulation was indicated by the ability
      of Z-DEVD-FMK, a caspase 3 inhibitor, to block the alpha6beta4-associated
      reduction in AKT/PKB levels in vivo, and by the ability of recombinant caspase 3 
      to promote the cleavage of AKT/PKB in vitro. In addition, the ability of
      alpha6beta4 to activate AKT/PKB could be restored in p53 wild-type carcinoma
      cells by inhibiting caspase 3 activity. These studies demonstrate that the p53
      tumor suppressor can inhibit integrin-associated survival signaling pathways.
FAU - Bachelder, R E
AU  - Bachelder RE
AD  - Division of Cancer Biology and Angiogenesis, Department of Pathology, Beth Israel
      Deaconess Medical Center, Boston, MA 02215, USA.
FAU - Ribick, M J
AU  - Ribick MJ
FAU - Marchetti, A
AU  - Marchetti A
FAU - Falcioni, R
AU  - Falcioni R
FAU - Soddu, S
AU  - Soddu S
FAU - Davis, K R
AU  - Davis KR
FAU - Mercurio, A M
AU  - Mercurio AM
LA  - eng
GR  - CA81697/CA/NCI NIH HHS/United States
GR  - AI39264/AI/NIAID NIH HHS/United States
GR  - CA80789/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  - United States
TA  - J Cell Biol
JT  - The Journal of cell biology
JID - 0375356
RN  - 0 (Antigens, Neoplasm)
RN  - 0 (Antigens, Surface)
RN  - 0 (Biomarkers, Tumor)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Epitopes)
RN  - 0 (Integrin alpha6beta4)
RN  - 0 (Integrins)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (Tumor Suppressor Protein p53)
RN  - EC 2.7.11.1 (AKT1 protein, human)
RN  - EC 2.7.11.1 (Protein-Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 3.4.22.- (CASP3 protein, human)
RN  - EC 3.4.22.- (Caspase 3)
RN  - EC 3.4.22.- (Caspases)
SB  - IM
MH  - Antigens, Neoplasm/metabolism
MH  - Antigens, Surface/*physiology
MH  - Biomarkers, Tumor
MH  - Caspase 3
MH  - Caspases/biosynthesis
MH  - Cell Survival/physiology
MH  - Colorectal Neoplasms
MH  - Enzyme Induction
MH  - Enzyme Inhibitors/pharmacology
MH  - Epitopes/metabolism
MH  - Humans
MH  - Integrin alpha6beta4
MH  - Integrins/*physiology
MH  - Protein-Serine-Threonine Kinases/*metabolism
MH  - *Proto-Oncogene Proteins
MH  - Proto-Oncogene Proteins c-akt
MH  - Signal Transduction/*physiology
MH  - Tumor Cells, Cultured
MH  - Tumor Suppressor Protein p53/*physiology
PMC - PMC2169339
EDAT- 1999/12/01 00:00
MHDA- 1999/12/01 00:01
CRDT- 1999/12/01 00:00
PHST- 1999/12/01 00:00 [pubmed]
PHST- 1999/12/01 00:01 [medline]
PHST- 1999/12/01 00:00 [entrez]
AID - 10.1083/jcb.147.5.1063 [doi]
PST - ppublish
SO  - J Cell Biol. 1999 Nov 29;147(5):1063-72. doi: 10.1083/jcb.147.5.1063.