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Por favor, use este identificador para citar o enlazar este ítem: http://documenta.ciemat.es/handle/123456789/2512

Título : Inhibition of pRb phosphorylation and cell-cycle progression by a 20-residue peptide derived from p16CDKN2/INK4A
Autor : Fåhraeus, Robin
Paramio, Jesus M
Ball, Katherin L
Lain, Sonia
Lane, David P
Palabras clave : pRb
p16
cell cycle
cdk4/6
penetratin
peptide mimetic
Fecha de publicación : 1-ene-1996
Editorial : ScienceDirect
Citación : Curr Biol . 1996 Jan 1;6(1):84-91. doi: 10.1016/s0960-9822(02)00425-6.
Resumen : Background: The CDKN2/INK4A tumour suppressor gene is deleted or mutated in a large number of human cancers. Overexpression of its product, p16, has been shown to block the transition through the G1/S phase of the cell cycle in a pRb-dependent fashion by inhibiting the cyclin D-dependent kinases cdk4 and cdk6. Reconstitution of p16 function in transformed cells is therefore an attractive target for anti-cancer drug design. Results: We have identified a 20-residue synthetic peptide--corresponding to amino acids 84-103 of p16--that interacts with cdk4 and cdk6, and inhibits the in vitro phosphorylation of pRb mediated by cdk4-cyclin D1. The amino-acid residues of p16 important for its interaction with cdk4 and cdk6 and for the inhibition of pRb phosphorylation were defined by an alanine substitution series of peptides. In normal proliferating human HaCaT cells and in cells released from serum starvation, entry into S phase was blocked by the p16-derived peptide when it was coupled to a small peptide carrier molecule and applied directly to the tissue culture medium. This cell-cycle block was associated with an inhibition of pRb phosphorylation in vivo. Conclusions: These results demonstrate that a p16-derived peptide can mediate three of the known functions of p16: firstly, it interacts with cdk4 and cdk6; secondly, it inhibits pRb phosphorylation in vitro and in vivo; and thirdly, it blocks entry into S phase. The fact that one small synthetic peptide can enter the cells directly from the tissue culture medium to inhibit pRb phosphorylation and block cell-cycle progression makes this an attractive approach for future peptidometic drug design. Our results suggest a novel and exciting means by which the function of the p16 suppressor gene can be restored in human tumours.
URI : http://documenta.ciemat.es/handle/123456789/2512
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