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36 Cell-Penetrating Peptides: Processes and Applications<br />

peptides also demonstrated that p16 inhibits α vβ 3 integrin-mediated cell spreading<br />

on vitronectin. 48<br />

Penetratin vectors have also been directed against downstream targets of pRb.<br />

Members of E2F transcription factors family are positive effectors of the cell cycle<br />

and downstream targets of pRb. Unphosphorylated pRb is able to sequester E2F,<br />

converting it from a transcriptional activator to a trancriptional re<strong>press</strong>or. Consequently,<br />

disruption of the pRb/E2F complex can lead to oncogenesis. Among proteins<br />

regulating E2F, cyclin A/CDK2 complexes neutralize E2F DNA-binding. Chen et al.<br />

have designed peptides corresponding to the cyclin A/CDK2-binding site on E2F. 49<br />

Coupled to penetratin, these peptides were able to kill transformed cells in which<br />

E2F was already deregulated by pRb inactivation. It is noteworthy that the same<br />

team has recently identified about 12 peptides able to antagonize in vitro E2F-1 and<br />

cyclin A activity. 50 The potential anticancer effect of cell-permeant versions of the<br />

peptides (coupled to penetratin) is presently tested on tumor cells.<br />

The tumor sup<strong>press</strong>or SSeCKS (sarc-sup<strong>press</strong>ed C kinase substrate) also blocks<br />

the G1/S transition through an interaction with cyclin D1. Internalization with<br />

penetratin of the SSeCKS sequence responsible for this interaction demonstrated<br />

that SSeCKS anchors cyclin D1 in the cytoplasm, thus giving a molecular basis to<br />

G1/S arrest induced by SSeCKS. 51<br />

Another study with penetratin-coupled antagonizing peptides was conducted to<br />

evaluate the role of the translation initiation factor eIF4E in cellular transformation. 52<br />

Over-ex<strong>press</strong>ion of eIF4E is oncogenic and found in a number of human cancers;<br />

eIF4E activity can be blocked by eIF4E binding proteins (4E-BPs). Peptides after<br />

eIF4E-binding motifs found in 4E-Bps and introduced into cells designed bound<br />

eIF4E and induced massive apoptosis, thus revealing an involvement of this protein<br />

in the control of cell death not related to its known role in mRNA translation.<br />

The tumor sup<strong>press</strong>or protein p53 is frequently targeted by oncoproteins in<br />

transformed cells. This is typically the case for adenovirus early region 1B protein<br />

(E1B), which binds and inactivates p53 through its sequestration in the cytoplasm.<br />

Penetratin-coupled peptides corresponding to the p53-binding site of E1B disrupted<br />

p53-E1B interaction allowing p53 nuclear addressing and restoring cell cycle arrest. 53<br />

Chemotherapy or radiation therapy activates p53-mediated processes in sensitive<br />

tissues. Thus p53 may be an appropriate target to reduce damages made to normal<br />

tissues during cancer therapies. Using a selection of genetic sup<strong>press</strong>or elements<br />

(GSE) from a library of randomly fragmented p53 cDNA, Mittelman and Gudkov<br />

have isolated p53-derived antagonizing peptides. 54 One of them, GSE56, was fused<br />

to penetratin and the fusion protein was shown to attenuate p53-mediated transactivation<br />

and reduce anticancer treatment side effects. 55<br />

Transcription factor c-Myc is a positive effector of cell proliferation; the misregulation<br />

of its activity can lead to cell transformation. To counteract its activity,<br />

Giorello et al. have developed penetratin-coupled inhibitory peptides. 56 These peptides<br />

were efficiently internalized in Myc-transformed human breast cancer cells and<br />

sup<strong>press</strong>ed their transformation characteristics. Efficiency was improved by synthesizing<br />

their retro-inverso forms; these new peptides were more potent (5 to 10 times)<br />

and more stable (30 to 35 times) than their natural counterparts. 57

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