PMID- 11960384
OWN - NLM
STAT- MEDLINE
DCOM- 20020510
LR  - 20161124
IS  - 0950-9232 (Print)
IS  - 0950-9232 (Linking)
VI  - 21
IP  - 13
DP  - 2002 Mar 27
TI  - Activation of caspase-3 and cleavage of Rb are associated with p16-mediated 
      apoptosis in human non-small cell lung cancer cells.
PG  - 2108-13
AB  - The p16 tumor suppressor gene is frequently inactivated in human cancer tissues 
      and cell lines. We previously reported that wild-type p16 expression from an 
      adenovirus vector (Adv/p16) induced p53-dependent apoptotic cell death in 
      non-small cell lung cancer (NSCLC) cell lines. Here we show the potential 
      mechanism of apoptosis induced by Adv/p16 infection. Infection of human NSCLC 
      cell line A549, which carries the wild-type p53 gene, with Adv/p16 resulted in 
      activation of caspase-3, accompanied by the cleavage of its substrate poly 
      (ADP-ribose) polymerase (PARP), on day 3 of infection. The retinoblastoma (Rb) 
      cell cycle regulator protein was also cleaved after activation of caspase-3; when 
      the levels of Rb significantly diminished, apoptosis began. When A549 cells were 
      pretreated with the caspase-inhibitory peptide N-acetyl-asp-Glu-Val-Asp-CHO 
      (aldehyde) (Ac-DEVD-CHO), Adv/p16-mediated apoptosis and Rb cleavage were greatly 
      inhibited. Furthermore, MDM2, a negative regulator of p53 expression was 
      upregulated 3 days after Adv/p16 infection, and MDM2 was subsequently cleaved by 
      caspase-3; MDM2 cleavage was inhibited by Ac-DEVD-CHO treatment. These data 
      implied that cleavage of Rb, in addition to activation of caspase-3, represented 
      a mechanism by which Adv/p16 induced apoptotic cell death in human NSCLC cells. 
      Our results support the clinical relevance of Adv/p16 as a treatment for p16-null 
      human NSCLC that express wild-type p53.
FAU - Katsuda, Koh
AU  - Katsuda K
AD  - Division of Surgical Oncology, Department of Surgery, Okayama University Graduate 
      School of Medicine and Dentistry, Okayama 700-8558, Japan.
FAU - Kataoka, Masafumi
AU  - Kataoka M
FAU - Uno, Futoshi
AU  - Uno F
FAU - Murakami, Takayoshi
AU  - Murakami T
FAU - Kondo, Tadashi
AU  - Kondo T
FAU - Roth, Jack A
AU  - Roth JA
FAU - Tanaka, Noriaki
AU  - Tanaka N
FAU - Fujiwara, Toshiyoshi
AU  - Fujiwara T
LA  - eng
GR  - 2P50-CA70970-04/CA/NCI NIH HHS/United States
GR  - CA16672/CA/NCI NIH HHS/United States
GR  - P01 CA78778-01A1/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 (Caspase Inhibitors)
RN  - 0 (Cyclin-Dependent Kinase Inhibitor p16)
RN  - 0 (Nuclear Proteins)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (Retinoblastoma Protein)
RN  - EC 2.3.2.27 (MDM2 protein, human)
RN  - EC 2.3.2.27 (Proto-Oncogene Proteins c-mdm2)
RN  - EC 3.4.22.- (CASP3 protein, human)
RN  - EC 3.4.22.- (Caspase 3)
RN  - EC 3.4.22.- (Caspases)
SB  - IM
MH  - Adenoviridae
MH  - *Apoptosis
MH  - Blotting, Western
MH  - Carcinoma, Non-Small-Cell Lung/enzymology/*metabolism/*pathology
MH  - Caspase 3
MH  - Caspase Inhibitors
MH  - Caspases/*metabolism
MH  - Cyclin-Dependent Kinase Inhibitor p16/*metabolism
MH  - Enzyme Activation
MH  - Genetic Vectors
MH  - Humans
MH  - Lung Neoplasms/enzymology/*metabolism/*pathology
MH  - *Nuclear Proteins
MH  - Protein Processing, Post-Translational
MH  - Proto-Oncogene Proteins/metabolism
MH  - Proto-Oncogene Proteins c-mdm2
MH  - Retinoblastoma Protein/*metabolism
MH  - Time Factors
MH  - Tumor Cells, Cultured
EDAT- 2002/04/18 10:00
MHDA- 2002/05/11 10:01
CRDT- 2002/04/18 10:00
PHST- 2001/09/24 00:00 [received]
PHST- 2001/12/18 00:00 [revised]
PHST- 2001/12/19 00:00 [accepted]
PHST- 2002/04/18 10:00 [pubmed]
PHST- 2002/05/11 10:01 [medline]
PHST- 2002/04/18 10:00 [entrez]
AID - 10.1038/sj.onc.1205272 [doi]
PST - ppublish
SO  - Oncogene. 2002 Mar 27;21(13):2108-13. doi: 10.1038/sj.onc.1205272.