Oncoproteins, release

A further influence on pRb function may be performed by viral oncoproteins. Tliese bind to the underphosphorylated form of pRb and compete with E2F for pRb binding (see Chapter 14). E2F is released from the inhibiting influence of pRb in this situation and can activate its target genes. 

Scale-up options include transformation of human MSCs over-expression using the MYC gene. Chen et al. (2011) showed that this transformation produces efficacious exosomes, and is also safe for therapeutic development given the MYC protein was present in the transformed cells but was not detectable in either the conditioned medium or the exosomes. Further, because oncoproteins, unlike the oncogene, cannot be replicated or amplified, possible tumorigenesis by exosomes released from MYC-transformed cells is further reduced. Another possible risk is the use of lentiviral vectors for the transformation of the stem cells, but given that the exosome and not the cell is used for therapy, this risk is also not present. 

The Bcl-2 family of oncoproteins is known to play an important role in apoptosis through their ability to regulate cytochrome c release from mitochondria [11,15]. The antiapoptotic proteins Bcl-2 and Bc1-Xl prevent cytochrome c release, whereas the proapoptotic family members (e.g.. Bad, Bid, Bik, Bax) facilitate cytochrome c efflux or block the protective effects of Bcl-2 and Bc1-Xl. The mechanism involved is unclear the Bcl-2 family proteins may interact directly with the MTP (mitochondrial permeability transition) protein complex (the PTPC) or form independent ionic pores in the outer mitochondrial membrane (Fig. 3). Nonetheless, cytochrome c-depen-dent caspase-3 activation and changes in the expression or phosphorylation state of Bcl-2 family proteins are taken as indicative of mitochondria-dependent apoptotic pathways. It is important to remember that other apoptogenic proteins are also present in the mitochondrial intermembrane space, including smac/ DIABLO and flavoprotein (AIF) [10,11,60]. The release stimuli for the latter factors, which are currently being elucidated, may also involve the permeability transition or the Bcl-2 family proteins [37]. 

The action of HDACs transcriptional repression pathways is not an academic issue, since HDAC inhibitors have long been known to be very potent cytostatic and differentiating agents. Thus, for example, a number of cell lines of cancerous origin can be driven to cease proliferation via the application of such HDAC inhibitors as tricho-statin A or sodium butyrate. In addition, oncoproteins that are produced as a result of chromosomal translocations in leukemias are known to depend on HDAC targeting for action compounds that force a release of HDAC from these chimeric proteins are successfiilly used in clinical practice to treat certain forms of leukemia. 

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