Growth-inhibitory and tumor- suppressive functions of p53 depend on its repression of CD44 expression.
The p53 tumor suppressor is a key mediator of cellular responses to various stresses. Here, we show that under conditions of basal physiologic and cell-culture stress, p53 inhibits expression of the CD44 cell-surface molecule via binding to a noncanonical p53-binding sequence in the CD44 promoter. This interaction enables an untransformed cell to respond to stress-induced, p53-dependent cytostatic and apoptotic signals that would otherwise be blocked by the actions of CD44. In the absence of p53 function, the resulting derepressed CD44 expression is essential for the growth and tumor-initiating ability of highly tumorigenic mammary epithelial cells. In both tumorigenic and nontumorigenic cells, CD44's expression is positively regulated by p63, a paralogue of p53. Our data indicate that CD44 is a key tumor-promoting agent in transformed tumor cells lacking p53 function. They also suggest that the derepression of CD44 resulting from inactivation of p53 can potentially aid the survival of immortalized, premalignant cells.
Godar
Samuel
S
Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
Ince
Tan A
TA
Bell
George W
GW
Feldser
David
D
Donaher
Joana Liu
JL
Bergh
Jonas
J
Liu
Anne
A
Miu
Kevin
K
Watnick
Randolph S
RS
Reinhardt
Ferenc
F
McAllister
Sandra S
SS
Jacks
Tyler
T
Weinberg
Robert A
RA
D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D004847:Epithelial Cells / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
C497483:CD44 protein, human; C081876:CKAP4 protein, human; D018960:Hyaluronan Receptors; D008565:Membrane Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53