Puma proteins

However, not all proapoptotic members are regulated post-translation-ally. Some, such as Noxa, Puma, and HRK, are regulated transcriptionally. Noxa and Puma are regulated by the p53 protein and, therefore, are critical... 

Other proteins from the Bcl-2 family are proapoptotic. The proapoptotic group is subclassified into BH3-only proteins (Bid), BH3-only with a transmembrane domain (Bad, Bim, Bik, Bmf, Hrk, Nox, or Puma), and multi-BH (BHl, 2, 3)... 

It was first observed in type Type 2 B-cell lymphoma that the translocation of the Bcl-2 gene leads to radical overexpression of Bcl-2 (10). The overproduction of Bcl-2 has been shown to be transforming (10). Members of the Bcl-2 protein family contain as many as four characteristically helical Bcl-2 homology motifs (BH1-BH4). Bcl-2 proteins are divided into classes, as prosurvival proteins (Bcl-2, Bc1-xl, Mc1-1, A-1, and Bcl-w), proapoptotic proteins (Bak and Bax), and proapoptotic proteins that contain only the BH3 motif (Bim, Bid, Puma, and Noxa) (3, 11). The manner in which the different Bcl-2 family members interact and the mechanisms by which cytochrome c release is initiated are unclear, but the central role of the Bcl-2 family in apoptosis, and the therapeutic potential of regulating these proteins, is well established. 

Villunger A, Michalak EM, Coultas F, Miillauer F, Bock G, Ausserlechner MJ, Adams JM, Strasser A. p53- and drug-induced apoptotic responses mediated by BH3-only proteins puma and noxa. Science 2003 302 1036-1038. 

Apoptosis is caused by the release or activation of one or more BH3 domain-only proteins (Fig. 13.9c, step 1). These initiating B 13-only proteins bind to a cytosolic heterodimer containing a Bcl-2 protein (step 2) and displace a previously bound BH3-only protein, Bid, BIM or PUMA (step 3). In the case of Bid, dissociation from a partner such as Bcl-2 may be mediated by proteolysis of the Bid N-terminal 60 amino acid residues, creating truncated Bid (tBid), which activates an effector protein. The BH3-only proteins are therefore activators of apoptosis that displace effector proteins (BAK or BAX) from a non-Bcl-2 partner on the cytosolic surface of mitochondria and endoplasmic reticulum (step 4). For example, BAK is attached to an outer mitochondrial membrane channel protein in a healthy cell. An activating BH3-only protein displaces BAK, which then self-aggregates into homodimers that burrow a hole in the mitochondrial or endoplasmic reticular membrane, releasing the contents (step 5). 

The list of genes activated by p53 includes many genes known to be important for apoptosis (review Hickman et al., 2002). Examples (Fig. 15.13) include members of the Bd-2 family of proteins, e. g., Bax, Bd-2, Puma, Nora, death receptors and their... 

Figure 18.7 A model for regulation of mitochondrial permeability by proteins of the Bcl-2 family. The association of pro-survival and pro-death members will result In the formation of an opened or closed channel resulting in either sequestration or release of pro-apoptotic factors from mitochondria. The BH3-only proteins, such as Bid or PUMA, play a critical role in tipping the balance in favor of cell death.

Cartron PF, Gallenne T, Bougras G et al. The first a-helix of Bax plays a necessary role in its ligand-induced activation by the BH3-only proteins Bid and PUMA. Mol Cell 2004 16 807-818. 

In response to ischemia and reperfusion, mitochondrial membranes undergo depolarization and elevated levels of Ca in the intermembrane space. The control of mitochondrial membrane depolarization depends, in part, on Bcl-2 family member proteins. The proapoptotic group of Bcl-2 members consists of the Bax-subfamily (Bax, Bak, and Bok) and the BH3-only proteins (Bid, Bim, Bik, Bad, Bmf, Hrk, Noxa, Puma, Blk, BNIP3, and Spike) (Cory and Adams, 2002 Mund et al., 2003). It appears that the main function of the Bcl-2 family proteins is to guard mitochondrial integrity and to control the release of mitochondrial proteins into the cytoplasm (Cory and Adams, 2002). It is believed that the proapoptotic Bax and Bak provoke or contribute to the perme-abilization of the outer mitochondrial membrane, either by forming channels by themselves (Antonsson et al., 2000) or by interacting with components such as VDAC (Tsujimoto and Shimizu, 2000). 

Yoshida K et al (2002) c-Abl tyrosine kinase regulates the human Rad9 checkpoint protein in response to DNA damage. Mol Cell Biol 22 3292-3300 You H et al (2006) FOX03a-dependent regulation of Puma in response to cytokine/growth factor withdrawal. J Exp Medicine 203 1657-1663... 

Mcl-l is a recognized major resistance factor in human cancer and Mcl-l over-expression has been linked to the pathogenesis of several cancers. Its anti-apoptotic properties are mechanistically related to its neutralizing interaction with BIM, BAK, NOXA and PUMA. ° Recently, a compelling Mcl-l BH3 stapled peptide has been reported to exhibit highly specificity and affinity to bind Mcl-l as well as effectively sensitizing cancer cells to caspase-dependent apoptosis in vitroJ An X-ray structure of Mcl-l complexed with this Mcl-l BH3 stapled peptide was also determined and showed inter-molecular contact of its hydrocarbon staple moiety with Mcl-l, accounting for the specificity versus other Bcl-2 family proteins. 

In our recent studies we reported that growth of winter-hardy Puma rye at cold-hardening temperatures resulted in various structural alterations in the thylakoid membranes. Specifically, we observed changes in the size distribution of freeze fracture particles on the EF fracture face (Huner et al, 1983) and changes also in the stability of the pigment-protein complexes associated with PSII (Elfman et al,... 

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