8/13/2019 AKT Diprint

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AKT/PKB phosphorylation of p21Cip/WAF1 enhances protein stability of

p21Cip/WAF1 and promotes cell survivalLi Y, Dowbenko D, Lasky LA.

Source

Department of Molecular Oncology, Genentech, Inc., San Francisco, California 9400, !

Abstract

p"#$Cip#%&'F#( $p"#(, a p)*+inuci-le protein, is a critical regulator of cell cycle an cell

surial. p"# -ins to an inhi-its -oth the D/' synthesis regulator proliferating cell nuclear

antigen an cyclin '%+CD1" comple2es. 3ecently, p"# has also -een shon to -e a positie

regulator of cell cycle progression as p"# is necessary for the assem-ly an actiation ofcyclin D#+CD14%5 comple2es. Furthermore, eleate p"# protein leels hae -een o-sere

in arious aggressie tumors as ell as lin6e to chemoresistance. 7ere e emonstrate that

p"# is irectly phosphorylate -y '18%1:, a surial 6inase that is hyperactiate in many

late stage tumors. 8o sites $8hr$#4)( an Ser$#45(( in the car-o2yl terminus of p"# are

phosphorylate -y '18%1: in itro an in io. hosphorylation of 8hr$#4)( inhi-its

C/' -ining, hereas phosphorylation of Ser$#45( significantly increases p"# protein

sta-ility. Glio-lastoma cell lines ith actiate '18%1: sho enhance p"# sta-ility, an

they are more resistant to ta2ol+meiate to2icity. Finally, '18%1: controls the assem-ly

of cyclin D#+CD14 comple2es through moulation of p"# an cyclin D# leels. 8hese ata

imply that enhance leels of p"# in tumors are ue, in part, to phosphorylation -y actiate

'18%1:. Furthermore, they suggest that one mechanism of '18%1: regulation of tumorcell surial an%or proliferation is to sta-ili;e p"# protein.

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