Smac (second mitochondrial activator of caspases) is released from the mitochondria during apoptosis to relieve inhibition of caspases by the inhibitor of apoptosis proteins (IAPs). The release of Smac antagonizes severalIAPs and assists the initiator caspase-9 and effector caspases (caspase-3, caspase-6, and caspase-7) in becoming active, ultimately leading to death of the cell. Translocation of Smac along with cytochrome c and other mitochondrial pro-apoptotic proteins represent important regulatory checkpoints for mitochondria-mediated apoptosis. Whether Smac and cytochrome c translocate by the same mechanism is not known. Here, we show that the time required for Smac efflux from the mitochondria of cells subjected to staurosporine-induced apoptosis is approximately four times longer than the time required for cytochrome c efflux. These results suggest that Smac and cytochrome c may exit the mitochondria by different pathways.Apoptosis (programmed cell death) plays key roles in both normal development and pathophysiology. Given the central importance of programmed cell death, apoptotic pathways are highly regulated, containing many checkpoints. Failures of regulatory checkpoints are pathogenic, the effects of which range from neurodegeneration to cancer (1, 2).During apoptosis, a family of cysteine proteases (caspases) are activated. Initiator caspases activate effector caspases, resulting in a caspase cascade that ultimately leads to cell death. The caspases are activated by two major signaling pathways, known as the "intrinsic" (mitochondrial) and "extrinsic" (death receptor) pathways. One early event in mitochondria-mediated apoptosis is the activation of the Bcl-2 family of proteins (3). They are important in controlling the release of regulatory mitochondrial proteins, which are sequestered in the mitochondrial intermembrane space (IMS) 1 until signaled. There is substantial debate about the mechanisms for release of mitochondrial proteins in apoptosis (3-5). During apoptosis, Smac in its processed form (21 kDa) is released from the mitochondria to interact with a variety of IAPs, including XIAP, c-IAP1, and ML-IAP (6 -8). IAPs inhibit the activity of caspases. Smac competes with caspase 9 for the same binding site on the BIR3 domain of XIAP. Smac also binds to the linker peptide between the BIR1 and BIR2 domains, sterically inhibiting caspase-3 and caspase-7 binding (9).The detailed mechanism of the translocation of Smac from the mitochondria to the cytosol remains unknown, and the kinetics of Smac release from a single cell have not been measured. While the specific Bcl-2 family members that cause the release of mitochondrial proteins remain controversial, one key question is: do Smac, cytochrome c, and other mitochondrial proteins exit the mitochondria on the same time scale and via the same pathway? Studies on cell populations indicate that Smac and cyt. c exit the mitochondria on the same general time scale, and a single transport mechanism has been suggested. However, such studies are not sufficien...
p73 is a member of the p53 gene family, which also includes p53 and p63. These proteins share sequence similarity and target genes but also have divergent roles in cancer and development. Unlike p53, transcription of the p73 gene yields multiple full-length (transactivation (TA) domain) and amino terminus-truncated (⌬N) isoforms. ⌬Np73 acts in a dominant negative fashion to inhibit the actions of TAp73 and p53 on their target genes, promoting cell survival and proliferation and suppressing apoptosis. The balance between TAp73 and its negative regulator, ⌬Np73, may therefore represent an important determinant of developmental cell fate. There is little if anything known regarding the developmental regulation of the p73 gene. In this study, we showed that TAp73 and ⌬Np73 exhibit reciprocal spatiotemporal expression and functions during nephrogenesis. TAp73 was predominantly expressed in the differentiation domain of the renal cortex in an overlapping manner with the vasopressin-sensitive water channel aquaporin-2 (AQP-2). Chromatin immunoprecipitation assays demonstrated that the endogenous AQP-2 promoter was occupied by TAp73 in a developmentally regulated manner. Furthermore TAp73 stimulated AQP-2 promoter-driven reporter expression. TAp73 also activated the bradykinin B2 receptor (B2R) promoter, a developmentally regulated gene involved in regulation of sodium excretion. The transcriptional effects of TAp73 on AQP-2 and B2R were independent of p53. In marked contrast to TAp73, ⌬Np73 isoforms were induced early in development and were preferentially expressed in proliferating nephron precursors. Moreover ⌬Np73 was a potent repressor of B2R gene transcription. We conclude that the p73 gene is developmentally regulated during kidney organogenesis. The spatiotemporal switch from ⌬Np73 to TAp73 may play an important role in the terminal differentiation program of the developing nephron.
For patients ineligible for cisplatin with definitive radiotherapy (CP-CRT) for locally advanced head and neck squamous cell carcinoma (LA-HNSCC), concurrent cetuximab (C225-RT) is a popular substitute. Carboplatin-based chemoradiation (CB-CRT) is another option; however, relative efficacies of CP-CRT, CB-CRT and C225-RT are unclear, particularly in the human papillomavirus (HPV)-unrelated population. We identified 316 patients with stage III-IVB cancers of the oropharynx (24.7%), larynx (58.2%) and hypopharynx (17.1%) undergoing definitive C225-RT (N = 61), CB-CRT (N = 74) or CP-CRT (N = 181). Kaplan-Meier and cumulative incidence functions were generated to estimate overall survival (OS), locoregional failure (LRF) and distant metastasis (DM). Cox proportional hazards were used to determine the association of survival endpoints with clinical characteristics. Respectively, 3-year cumulative incidences for CP-CRT, CB-CRT and C225-RT were: LRF (0.19, 0.18 and 0.48, p ≤ 0.001), DM (0.17, 0.12 and 0.25, p = 0.32). Kaplan-Meier estimates for 3 year OS were: CP-CRT: 71%; CB-CRT: 59% and C225-RT: 54%; p = 0.0094. CP-CRT (hazard ratio [HR] 0.336; 95% confidence interval [CI] 0.203-0.557, p < 0.01) and CB-CRT (HR 0.279; 95% CI 0.141-0.551, p < 0.01) were associated with reduced hazard for LRF on multivariable analysis. CP-CRT (HR 0.548; 95% CI 0.355-0.845, p < 0.01) and CB-CRT (HR 0.549; 95% CI 0.334-0.904, p = 0.02) were associated with a reduced hazard for death on multivariable analysis. Propensity matching confirmed reduced hazards with a combined CP/CB-CRT group compared to C225-RT for LRF: HR 0.384 (p = 0.018) and OS: HR 0.557 (p = 0.045) and CB-CRT group *T.H.B. and C.B. are co-first authors † N.C. and A.D.B. are co-senior authors Cancer Therapy and Prevention compared to C225-RT for LRF: HR 0.427 (p = 0.023). In conclusion, CB-CRT is an effective alternative to CP-CRT in HPV-unrelated LA-HNSCC with superior locoregional control and OS compared to C225-RT.What's new? While head and neck squamous cell carcinoma that are caused by human papillomavirus can be treated relatively well, virusnegative tumors have a poor prognosis. In this large multi-institutional study, the authors found that cisplatin-and carboplatin-based regimens-in concurrent chemoradiotherapy-were superior to antibody-based therapies, with carboplatinbased regimens representing a more tolerable alternative for patients with virus-negative tumors.
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