CD40 activation mediates p53-dependent cell cycle regulation in human multiple myeloma cell lines.
It has been reported that the activation of multiple myeloma (MM) cells by CD40 induces proliferation, growth arrest, and apoptosis. To determine whether the biologic sequelae of CD40 activation in MM cells depends on p53 function, we identified temperature-sensitive p53 mutations in the RPMI 8226 (tsp53E285K) and the HS Sultan (tsp53Y163H) MM cell lines. These cells were then used as a model system of inducible wtp53-like function because wild-type-like p53 is induced at permissive (30 degrees C) but not at restrictive (37 degrees C) temperatures. Using p21-luciferase reporter assays, we confirmed that CD40 induces p53 transactivation in RPMI 8226 and HS Sultan cells cultured under permissive, but not restrictive, conditions. Furthermore, CD40 activation of these MM cells under permissive, but not restrictive, temperatures increased the expression of p53 and p21 mRNA and protein. Importantly, CD40 activation induced the proliferation of RPMI 8226 and HS Sultan cells at restrictive temperatures and growth arrest and increased subG1 phase cells at permissive temperatures. These data confirmed that CD40 activation might have distinct biologic sequelae in MM cells, depending on their p53 status.
Teoh
G
G
Department of Adult Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Tai
Y T
YT
Urashima
M
M
Shirahama
S
S
Matsuzaki
M
M
Chauhan
D
D
Treon
S P
SP
Raje
N
N
Hideshima
T
T
Shima
Y
Y
Anderson
K C
KC
D016475:3T3 Cells; D000818:Animals; D019013:CD40 Antigens / Q000502:physiology*; D002453:Cell Cycle / Q000502:physiology*; D002455:Cell Division; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D016158:Genes, p53; D006801:Humans; D008213:Lymphocyte Activation; D051379:Mice; D009101:Multiple Myeloma / Q000473:pathology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012334:RNA, Neoplasm / Q000096:biosynthesis / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics; D013696:Temperature; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
D019013:CD40 Antigens; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D011993:Recombinant Fusion Proteins; D016159:Tumor Suppressor Protein p53