Tour-de-Force

More documents

Recommendations

Info

Tour-de-Force: Interplay between Mitochondria and Cell Cycle Progression Fall 2007Studies have been conducted, revealing an increased level of PGC-1α during muscle regeneration, adynamic and complex event involving phagocytosis of muscle debris, revascularization, activation,proliferation and differentiation (Duguez et al., 2001). More specifically a study done by Duguez et al.,investigated and hypothesized that mitochondrial biogenesis would be stimulated during skeletal muscleregeneration through PGC-1α (Duguez et al., 2001).The study mentioned above focused on skeletal muscle and its capacity to regenerate after injury. Thestudy revealed that during muscle regeneration there was marked increase in mitochondrial respirationafter injection of bupivacaine (a chemical agent frequently used to study muscle regeneration due to itsstimulus for rapid muscle fiber necrosis (Duguez et al., 2001)). The research also visually examined themuscle regeneration process, by means of histochemical analysis of the tissues (Figure 3.2) Along sidethis the levels of mtTFA (mitochondrial transcription factor A) as well as PGC-1α mRNA levels wereassessed (Figure 3.3). At 10 days post bupivacaine injection there is a marked increase in the expressionof PGC-1α, consistent with the regeneration of muscle fibers and mtTFA observed in Figure 3.2c at 10days post bupivacaine injection. (Duguez et al., 2001)This indicates that PGC-1α is involved in the regeneration process of the muscle fibers in relation to anincreased rate of mitochondrial biogenesis.Figure 3.3:Effects of bupivacaine on mtTFA and PGC-1 mRNAlevel. During the time post-bupivacaine injection,increased levels of PGC-1α were as well asincreased levels of mtTFA.Source: Duguez et al., 2001Figure 3.2:Histochemical analysis of necrosis andmuscle regeneration. a) control tissue b) 3days post bupivacaine injection c)10 dayspost bupivacaine injection d) 35 days postbupivacaine injectionSource: Duguez et al., 2001It is relevant to investigate the functions of the PPAR family in terms of cell cycle proliferation as they havepalpable and important roles such as provoking mitochondrial biogenesis. Muscle fibers of adultorganisms are terminally differentiated and have lost the ability to proliferate. Nevertheless, they containan accumulation of satellite cells (myogenic stem cells) which are able to proliferate, inducing hypertrophyas well as muscle regeneration upon stimulations such as injury or increased physical activity (Li et. al.,2006). As is characteristic of cellular proliferation, increased ATP as well as mitochondrial biogenesis isrequired, processes which are under the control of the PPAR family proteins. Connections have beensuggested and PRC has been identified as having the characteristics of an immediate early gene (Duguezet. al. 2001; Melloul & Stoffel, 2004; Vercauteren et. al. 2006) nonetheless, there are no direct studieslinking the activation of all the PPAR family proteins directly to the cell cycle.p38 MAPK and PGC-1αResearches conducted in the field of the PPAR family have identified various upstream factors which areinvolved in the activation of these coactivators. Initially, researchers established that the posttranslationalcontrol of PGC-1α was conducted via a negative regulatory region, located between amino acids 170 andSCI 332 Advanced Molecular Cell Biology Research Proposal 60
Tour-de-Force: Interplay between Mitochondria and Cell Cycle Progression Fall 2007350 (Fan et al., 2003) that decreased the effectiveness of the transcriptional activation domain at the N-terminus (see Figure 3.1) (Melloul and Stoffel, 2004). It was noted that this inhibitory effect wasdiminished by phosphorylation of the negative regulatory region, specifically at three residues Thr262,Ser265, and Thr298 by a member of the mitogen-activated protein kinase (MAPK) family, greatlystabilizing PGC-1α (Melloul and Stoffel, 2004).A signaling pathway through p38MAPK was established to activate PGC-1α(Fan et al., 2004). This research also identifieda repressor p160 myb of PGC-1α. In responseto cytokine and growth factor signaling (Figure3.4), the p38 MAPK pathway is activatedultimately disrupting the binding of the p160mybrepressor of PGC-1α and lifting theinhibitory effect (Melloul and Stoffel, 2004).Although the p38 MAPK pathway is primarilyinvolved in stress response as well asapoptosis and differentiation, it has also beenimplicated and linked to proliferation in variouscell types. A study done by Petersen et. al.disclosed that proliferation in immature Sertolicells was mediated via p38 MAPK uponstimulation of IL-1a (Interleukin-1 an effectivegrowth factor for immature Sertoli cells).Nevertheless, there is no experimentaldata which links the proliferative role of p38MAPK by means of PGC-1α activation to thecell cycle.Figure 3.4:Activation of PGC-1α by p38 MAPKSource: Melloul and Stoffel, 2004PRCOne of the sister proteins of PGC-1α and β is PRC. PRC shares a lot of structural similarities with theother two isoforms, but differs from them by being ubiquitously expressed in various tissues. Unlike PGC-1α for example, PRC is not induced during adaptive thermogenesis (Vercauteren et al., 2006).On the contrary, PRC is upregulated during G0-G1 transition upon serum induction in fibroblast cellsswitching from quiescent to proliferative, making it particular as there are not a lot of serum-inducibletranscriptional coactivators known (Vercauteren et al., 2006).Additionally, it was observed that PRC is downregulated when cells move back into the G0 stateby either serum withdrawal or contact inhibition implying that PRC is a growth-regulated coactivator(Vercauteren et al., 2006).The study by Vercauteren et al. also established that PRC can be classified as an immediate early gene,capable of complexing in an identical manner on the same binding sites with CREB and NRF-1 and that itoccupies the cytochrome c promoter in vivo. The binding of PRC in a complex with CREB and NRF-1allows for the transcription of cytochrome c, an important element of the mitochondrial electron transportchain (Vercauteren et al., 2006). PRC has been identified as having the characteristics of an immediateearly gene product, as experimental data elucidate that PRC induction is rapid at both the protein andmRNA level, as a result of serum stimulation of quiescent fibroblasts (Vercauteren et al., 2006; Anderssonand Scarpulla , 2001). Furthermore it has been proposed that PRC deficiency may disrupt early postnataldevelopment as PRC directed growth is dependent on cellular conditions in which energy is primarilyobtained by means of oxidative phosphorylation; an enhanced state during postnatal respiratory growth, inwhich tissues depend largely on oxidative energy (Vercauteren et al., 2006). To this day there is noexperimental data that states which part of the cell cycle and which genes would be affected by adominant negative inhibition of PRC.SCI 332 Advanced Molecular Cell Biology Research Proposal 61
Page 1 and 2:
Tour-de-ForceInterplay between mito
Page 3 and 4:
Tour-de-Force: Interplay between Mi
Page 5 and 6:
Page 7 and 8:
Page 9 and 10: Tour-de-Force: Interplay between Mi
Page 59: Tour-de-Force: Interplay between Mi
Page 111 and 112:
Page 113 and 114:
Page 115 and 116:
Page 117 and 118:
show all

Tour-de-Force

You also want an ePaper? Increase the reach of your titles

Delete template?

Save as template?