Placental transforming growth factor-beta is a downstream mediator of the growth arrest and apoptotic response of tumor cells to DNA damage and p53 overexpression.
The p53 tumor suppressor gene and members of the transforming growth factor-beta (TGF-beta) superfamily play central roles in signaling cell cycle arrest and apoptosis (programmed cell death) in normal development and differentiation, as well as in carcinogenesis. Here we describe a distantly related member of the TGF-beta superfamily, designated placental TGF-beta (PTGF-beta), that is up-regulated in response to both p53-dependent and -independent apoptotic signaling events arising from DNA damage in human breast cancer cells. PTGF-beta is normally expressed in placenta and at lower levels in kidney, lung, pancreas, and muscle but could not be detected in any tumor cell line studied. The PTGF-beta promoter is activated by p53 and contains two p53 binding site motifs. Functional studies demonstrated that one of these p53 binding sites is essential for p53-mediated PTGF-beta promoter induction and specifically binds recombinant p53 in gel mobility shift assays. PTGF-beta overexpression from a recombinant adenoviral vector (AdPTGF-beta) led to an 80% reduction in MDA-MB-468 breast cancer cell viability and a 50-60% reduction in other human breast cancer cell lines studied, including MCF-7 cells, which are resistant to growth inhibition by recombinant wild-type p53. Like p53, PTGF-beta overexpression was seen to induce both G(1) cell cycle arrest and apoptosis in breast tumor cells. These results provide the first evidence for a direct functional link between p53 and the TGF-beta superfamily and implicate PTGF-beta as an important intercellular mediator of p53 function and the cytostatic effects of radiation and chemotherapeutic cancer agents.
Li
P X
PX
Divisions of Experimental Therapeutics and Molecular and Structural Biology, Ontario Cancer Institute, Princess Margaret Hospital, University Health Network, Toronto, Ontario, Canada.
Wong
J
J
Ayed
A
A
Ngo
D
D
Brade
A M
AM
Arrowsmith
C
C
Austin
R C
RC
Klamut
H J
HJ
D000256:Adenoviridae / Q000378:metabolism; D017209:Apoptosis; D015152:Blotting, Northern; D001943:Breast Neoplasms / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage; D018076:DNA, Complementary / Q000378:metabolism; D016158:Genes, p53 / Q000235:genetics; D005822:Genetic Vectors / Q000378:metabolism; D006133:Growth Substances / Q000378:metabolism*; D006801:Humans; D011257:Pregnancy Proteins / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D017422:Sequence Analysis, DNA; D013997:Time Factors; D014018:Tissue Distribution; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis*; D015854:Up-Regulation / Q000187:drug effects / Q000528:radiation effects
D018076:DNA, Complementary; D006133:Growth Substances; D011257:Pregnancy Proteins; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53