A Copper-Based Metal-Organic Framework for Selective Separation of C2 Hydrocarbons from Methane at Ambient Conditions: Experiment and Simulation.

C2 hydrocarbon separation from methane represents a technological challenge for natural gas upgrading. Herein, we report a new metal-organic framework, [Cu2L(DEF)2]·2DEF (UNT-14; H4L = 4,4',4″,4‴-((1E,1'E,1″E,1‴E)-benzene-1,2,4,5-tetrayltetrakis(ethene-2,1-diyl))tetrabenzoic acid; DEF = N,N-diethylformamide; UNT = University of North Texas). The linker design will potentially increase the surface area and adsorption energy owing to π(hydrocarbon)-π(linker)/M interactions, hence increasing C2 hydrocarbon/CH4 separation. Crystallographic data unravel an sql topology for UNT-14, whereby [Cu2(COO)4]···[L]4- paddle-wheel units afford two-dimensional porous sheets. Activated UNT-14a exhibits moderate porosity with an experimental Brunauer-Emmett-Teller (BET) surface area of 480 m2 g-1 (vs 1868 m2 g-1 from the crystallographic data). UNT-14a exhibits considerable C2 uptake capacity under ambient conditions vs CH4. GCMC simulations reveal higher isosteric heats of adsorption (Qst) and Henry's coefficients (KH) for UNT-14a vs related literature MOFs. Ideal adsorbed solution theory yields favorable adsorption selectivity of UNT-14a for equimolar C2Hn/CH4 gas mixtures, attaining 31.1, 11.9, and 14.8 for equimolar mixtures of C2H6/CH4, C2H4/CH4, and C2H2/CH4, respectively, manifesting efficient C2 hydrocarbon/CH4 separation. The highest C2 uptake and Qst being for ethane are also desirable technologically; it is attributed to the greatest number of "agostic" or other dispersion C-H bond interactions (6) vs 4/2/4 for ethylene/acetylene/methane.

Oncological Clearance Following Resection of the Carcinoma Rectum: A Comparison between Laparoscopic and Open Anterior Resection.

Till the day the rectal cancer deaths in the world is in eighth position. For rectal cancer surgery, short-term benefits are expected to be similar for laparoscopic resection of rectum (LRR) and open resection of rectum (ORR). In Bangladesh though the rectal cancer is the sixteenth most common cause of cancer deaths, there is lack of data regarding outcomes of laparoscopic and open surgical approaches for carcinoma rectum. Purpose of study was to compare oncopathological outcomes by quality of surgical resection between LRR and ORR groups. The quasi experimental study was conducted among 46 subjects who attended in the Department of Colorectal Surgery, Bangabandhu Sheikh Mujib Medical University, Bangladesh from July 2020 to June 2021 with rectal adenocarcinoma within 15cm from the anal verge. Equal number of subjects were allocated for LRR and ORR group. Oncopathological end points such as circumferential resection margin (CRM), distal resection margin (DRM), lymph nodes and quality of mesorectal excision were assessed and compared. Here every patients have given their written consent for this study. Mean age of the subjects for LRR and ORR were 45.47±12.66 and 44.47±12.48 years respectively. Majority of the subjects were in age above 40 years (67.0%). The proportion of male (56.5%) were higher than those of female (43.5%). The complete resection was better in LRR (91.3%) than ORR (87.0%) group though statistically not significant. CRM was lower in LRR (0.0%) than ORR (13.0%) group in respect of frequency distribution. DRM was negative for both LRR and ORR group (95.7% each) and it was not statistically significant. ORR met the National Comprehensive Cancer Network (NCCN) criteria of harvesting 12 lymph nodes were as in LRR group 10 lymph nodes were harvested. The mean harvested lymph nodes were 12.2±5.55 and 10.1±5.55 in LRR and ORR group respectively. The study demonstrated that LRR is better (though statistically not significant) in respect of complete resection and CRM while in harvesting lymph nodes, ORR met the NCCN criteria but LRR does not. There is no difference observed regarding DRM in both groups. On oncopathological point of view both the group showed almost equally effective results. Laparoscopic surgery can be opted as the standard operative technique for surgical management of rectal cancer.

First case of focal epilepsy associated with SARS-coronavirus-2.

A healthy patient presented to Klinikum Altmühlfranken Weißenburg Hospital, Germany, with two morning attacks of painful muscle spasm in the left upper and lower limbs, without altered consciousness. Full examinations, radiological imaging, electroencephalography, lumbar puncture, and autoimmune profile were either normal or not consistent with patient's complaint. Subsequent epileptic episodes were observed on admission day and the following days; thus, the patient was diagnosed with focal epilepsy. The patient started to develop a fever and severe cough on day 4, and SARS-coronavirus-2 was confirmed through a nasopharyngeal swap. She received anticonvulsants and symptomatic treatments and completely recovered. This report emphasizes the potential nervous system involvement in severe acute respiratory syndrome-coronavirus-2 pathogenesis.

Compliance with standard precautions among baccalaureate nursing students in a Saudi university: A self-report study.

Meticulous observance of standard infection control precautions by health care providers is strongly recommended for every patient encounter. Assessment of nursing students' compliance should be carried out regularly in order to ensure adherence to protocols. Thus, this study was conducted to assess self-reported compliance with standard precautions among baccalaureates in nursing students in a Saudi university. A convenience sample of 236 nursing students was surveyed in this cross-sectional, self-reported study, using the Compliance with Standard Precaution Scale Arabic version (CSPS-A). Independent t-test and one-way analyses of variance (ANOVA) were performed to examine the differences on compliance. A multiple regression analysis was performed to identify the factors affecting compliance. The overall compliance rate was 61.0%. The students reported highest compliance in disposing used sharp instruments and other sharp objects into sharps-only boxes, while the lowest compliance rate in using water only for hand washing. Significant differences in compliance were observed when respondents were grouped according to their demographic characteristics. Cultivating a supportive culture of adherence to infection control precautions among nursing students is of paramount importance. The clinical environment should be supportive of a culture where strict compliance with the control and prevention of infection is of prime importance.

Negative regulation of RNA-binding protein HuR by tumor-suppressor ECRG2.

Esophageal cancer-related gene 2 (ECRG2) is a newer tumor suppressor whose function in the regulation of cell growth and apoptosis remains to be elucidated. Here we show that ECRG2 expression was upregulated in response to DNA damage, and increased ECRG2 expression induced growth suppression in cancer cells but not in non-cancerous epithelial cells. ECRG2-mediated growth suppression was associated with activation of caspases and marked reduction in the levels of apoptosis inhibitor, X chromosome-linked inhibitor of apoptosis protein (XIAP). ECRG2, via RNA-binding protein human antigen R (HuR), regulated XIAP mRNA stability and expression. Furthermore, ECRG2 increased HuR ubiquitination and degradation but was unable to modulate the non-ubiquitinable mutant form of HuR. We also identified missense and frame-shift ECRG2 mutations in various human malignancies and noted that, unlike wild-type ECRG2, one cancer-derived ECRG2 mutant harboring glutamic acid instead of valine at position 30 (V30E) failed to induce cell death and activation of caspases. This naturally occurring V30E mutant also did not suppress XIAP and HuR. Importantly, the V30E mutant overexpressing cancer cells acquired resistance against multiple anticancer drugs, thus suggesting that ECRG2 mutations appear to have an important role in the acquisition of anticancer drug resistance in a subset of human malignancies.

Protective ileostomy in low anterior resection for rectal cancer -- can it be avoided?

The necessity of a protective ileostomy in patients subjected to low anterior resection for rectal cancer has been discussed controversially. This prospective observational study was carried out to see the outcome of low anterior resection without a covering ileostomy. Forty patients underwent low anterior resection for primary rectal carcinoma in mid and distal rectum without any covering ileostomy from January 2007 and June 2010 in the department of Surgery of Bangabandhu Sheikh Mujib Medical University and two other private hospitals in Dhaka city. The primary objective of the study was to demonstrate clinical anastomotic leak rate, reoperation rate and morbidity and mortality related to leak. Thirty two male and eight female patients underwent low anterior resection for primary rectal carcinoma. Median age was 53 years (range 23-67). Majority of the tumors were located within 10cm from anal verge and most of the cases were in Duke's stage B and C. One male patient (overall 2.5%) developed clinical anastomotic leakage, but responded well to conservative treatment. There was no 30 days mortality. Covering ileostomy can be avoided in selected patients with low anterior resection for primary carcinoma in mid and distal rectum.

Potential tumor-suppressive role of monoglyceride lipase in human colorectal cancer.

Human monoglyceride lipase (MGL) is a recently identified lipase and very little is known about its regulation and function in cellular regulatory processes, particularly in context to human malignancy. In this study, we investigated the regulation and function of MGL in human cancer(s) and report that MGL expression was either absent or reduced in the majority of primary colorectal cancers. Immunohistochemical studies showed that reduction of MGL expression in the colorectal tumor tissues predominantly occurred in the cancerous epithelial cells. MGL was found to reside in the core surface of a cellular organelle named 'lipid body'. Furthermore, it was found to interact selectively with a number of phospholipids, including phosphatidic acid and phosphoinositol(3,4,5)P3, phosphoinositol(3,5)P2, phosphoinositol(3,4)P2 and several other phosphoinositides, and among all phosphoinositides analyzed, its interaction with PI(3,4,5)P3 was found to be the strongest. In addition, overexpression of MGL suppressed colony formation in tumor cell lines and knockdown of MGL resulted in increased Akt phosphorylation. Taken together, our results suggest that MGL plays a negative regulatory role in phosphatidylinositol-3 kinase/Akt signaling and tumor cell growth.

Celecoxib and a novel COX-2 inhibitor ON09310 upregulate death receptor 5 expression via GADD153/CHOP.

Cyclooxygenase-2 (COX-2) inhibitors are promising anticancer agents but their long-term use at high doses is associated with adverse cardiovascular events. The molecular mechanisms underlying the anticancer or toxic cardiovascular effects of COX-2 inhibitors remain unknown. Here we report that COX-2-selective celecoxib and a novel COX-2 inhibitor ON09310 upregulate death receptor 5 (DR5) and cooperate with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), the ligand for DR5, to induce apoptosis in COX-2-positive and -negative cancer cells. We also show that both agents engage GADD153/CHOP to transcriptionally upregulate DR5 expression; GADD153/CHOP is a C/EBP homologous transcription factor implicated in cellular stress response and apoptosis. Based on our results, we propose that (1) these agents appear to mediate their effects, at least in part, by engaging GADD153/CHOP to activate DR5-dependent apoptotic pathway and (2) their regulation of GADD153/CHOP and DR5 expression appears to occur independent of their COX-2 inhibitory effects. Our results also indicate that ON09310 is generally more potent than celecoxib and, at lower concentration, strongly cooperates with TRAIL to induce apoptosis. Taken together, our findings form the basis for future in-depth studies to further explore the utility of TRAIL and/or agonistic anti-DR5 antibodies in combination with low-dose COX-2 inhibitors as a rational approach for cancer prevention and treatment.

Mitotic kinase Aurora-A phosphorylates RASSF1A and modulates RASSF1A-mediated microtubule interaction and M-phase cell cycle regulation.

RASSF1A (RAS-association domain family 1, isoform A) is a newer tumor suppressor that binds to and stabilizes microtubules as well as induces M-phase cell cycle arrest. Several other proteins that interact with and stabilize microtubules also undergo mitotic phase phosphorylation to regulate microtubule dynamics and M-phase cell cycle progression. Currently, however, there is a paucity of information regarding the phosphorylation status of RASSF1A and its regulation during mitosis. In this study, for the first time, we demonstrate that Aurora-A is a RASSF1A kinase and, to the best of our knowledge, this is also the first study reporting the identification of a kinase for RASSF1A. We show that the mitotic kinase Aurora-A directly interacts with and phosphorylates RASSF1 and that RASSF1A is phosphorylated by Aurora-A during mitosis. These findings therefore link an important oncogenic mitotic kinase to regulate RASSF1A tumor suppressor. Aurora-A appears to phosphorylate RASSF1A at Threonine202 and/or Serine203 that reside within the known microtubule-binding domain of RASSF1A. Substitutions of these residues with glutamic acid at both positions, mimicking constitutive phosphorylation of RASSF1A, disrupt RASSF1A interactions with microtubules and abolish its ability to induce M-phase cell cycle arrest. Our results further demonstrate that Aurora-A overexpression also interferes with RASSF1A-mediated growth suppression. In view of our results, we propose that Aurora-A-mediated phosphorylation of RASSF1A is a novel mechanism that regulates the ability of this tumor suppressor to interact with microtubules and modulate M-phase cell cycle progression.

Transcriptional upregulation of PUMA modulates endoplasmic reticulum calcium pool depletion-induced apoptosis via Bax activation.

PUMA, a key mediator of p53-induced apoptosis, is a BH3-only domain proapoptotic protein that localizes to mitochondria and interacts with antiapoptotic Bcl-2 and Bcl-X(L). Recent evidence implicates Bax to be an important mediator of PUMA-activated apoptotic signals. We have previously demonstrated that Bax deficiency significantly affects thapsigargin (TG)-mediated endoplasmic reticulum calcium pool depletion-induced apoptosis. We now present evidence that TG upregulates PUMA expression and that although Bax-deficient cells exhibit resistance to TG, Bax deficiency does not attenuate TG upregulation of PUMA expression. Furthermore, TG transcriptionally upregulates PUMA expression in a p53-independent manner and that PUMA-deficient cells are more resistant to undergo TG-induced apoptosis than the PUMA-proficient counterparts. Thus, our results demonstrate that TG engages PUMA and Bax for full transduction of apoptotic signals and both PUMA and Bax appear to exist in the same TG-activated apoptotic pathway in which PUMA may reside upstream of Bax.

Sulindac sulfide-induced apoptosis involves death receptor 5 and the caspase 8-dependent pathway in human colon and prostate cancer cells.

Sulindac is the most extensively investigated clinically relevant chemopreventive nonsteroidal anti-inflammatory drug. Sulindac sulfide is one of the major metabolites of sulindac that is believed to mediate its antitumorigenic effects by inducing apoptosis. Recent evidence suggests that sulindac sulfide engages the mitochondrial pathway involving caspase 9 and Bax to mediate its apoptotic effects [Zhang et al., Science (Wash. DC), 290: 989-992, 2000]. In this report, we demonstrate that sulindac sulfide also engaged the membrane death receptor (DR) pathway to mediate apoptosis. Sulindac sulfide up-regulated DR5 and activated the proximal caspase 8 in various different colon and prostate cancer cell lines. Sulindac sulfide specifically up-regulated the DR5 levels but had no effect on the levels of other DRs including DR4, Fas, and tumor necrosis factor receptor 1. To further delineate the role of DR5 in sulindac sulfide-induced apoptosis, we used JCA-1 prostate cancer cells that are deficient in mounting a Fas and tumor necrosis factor receptor 1-dependent apoptotic response but are proficient in mediating DR5-dependent apoptosis. JCA-1 cells were stably transfected with dominant-negative Fas-associated death domain to block the flow of apoptotic signals originating from the endogenous DR5, and sulindac sulfide-induced apoptosis was investigated. Our results indicated that by blocking the DR5-dependent apoptotic pathway, dominant-negative Fas-associated death domain did indeed inhibit sulindac sulfide-induced apoptosis. Furthermore, exogenous tumor necrosis factor-related apoptosis-inducing ligand, the ligand for DR5, also potentiated sulindac sulfide-induced apoptosis in all of the cell lines tested, thereby further supporting the involvement of DR5 in sulindac sulfide-induced apoptosis. Thus, our results demonstrate that sulindac sulfide also engages the membrane DR pathway involving DR5 and proximal caspase 8 to induce apoptosis.

Activation of Gadd34 by diverse apoptotic signals and suppression of its growth inhibitory effects by apoptotic inhibitors.

DNA damage has many cellular consequences including, in some cases, apoptosis. Expression of Gadd34 was shown to be increased by ionizing radiation only in cells that undergo rapid apoptosis following this treatment. The effects of various other apoptosis-inducing agents as well as apoptosis-inhibiting genes on regulation of Gadd34 were investigated. In many cell types, agents which have been reported to lead to increased intracellular ceramide levels led to an increase in Gadd34 transcript levels. These included TNFalpha, the ceramide analog C-2 ceramide, dimethyl sphingosine and anti-Fas antibody as well as ionizing radiation. Induction of Gadd34 by ionizing radiation was coincident with the onset of apoptosis and increased as apoptosis progressed. In a short-term transfection assay, more than 30% of Gadd34-transfected cells exhibited nuclear fragmentation by 48 hours. Apoptosis, as well as induction of Gadd34 by apoptotic stimuli, was attenuated by the apoptosis inhibitors, Bcl-2, cowpox virus CrmA and herpes simplex virus ICP34.5. Thus, activation of Gadd34 is a downstream event in apoptotic signaling pathways and may directly contribute to the apoptotic process.

Effects and expression of TRAIL and its apoptosis-promoting receptors in human pancreatic cancer.

Pancreatic cancer cells are usually resistant to apoptosis mediated by tumor necrosis factor (TNF)-alpha or FasL, and their toxicity towards normal cells hampers their application for therapeutic use. TNF-related apoptosis-inducing ligand (TRAIL), a novel member of the TNF family, triggers apoptosis in a variety of malignant cells, but exhibits less cytotoxicity in normal cells. To investigate the therapeutic potential of TRAIL, we analyzed the expression of TRAIL and its apoptosis-inducing receptors (DR4 and DR5) in the normal and cancerous human pancreas, and the sensitivity of pancreatic cancer cells to TRAIL cytotoxicity. TRAIL, DR4 and DR5 mRNA levels were concomitantly increased in pancreatic cancers compared with normal controls (P<0.01), and there were positive correlations between the expression levels of TRAIL and DR4, TRAIL and DR5 and between DR4 and DR5 mRNA (r=0.85, r=0.87, r=0.91; P<0.01). Immunostaining revealed the presence of the corresponding proteins frequently within the same cancer cells. In five pancreatic cancer cell lines, TRAIL, DR4 and DR5 mRNA expression was detectable at various levels. However, independent of the presence of DR4 and DR5, TRAIL cytotoxicity assays revealed that pancreatic cancer cells showed a significantly lower sensitivity (LD(50)>85 ng/ml) to TRAIL treatment than Jurkat T lymphoma cells (LD(50)=7.2 ng/ml). These findings show that pancreatic cancers are insensitive towards TRAIL-mediated apoptosis despite expression of TRAIL and its receptors, suggesting the presence of mediators which inhibit the TRAIL cell-death-inducing pathway in pancreatic cancer cells.

Death and decoy receptors and p53-mediated apoptosis.

Recently, several tumor necrosis factor receptor 1 (TNF-R1) and Fas-related death receptors have been discovered and include DR3, DR4, DR5 and DR6. These receptors contain an extracellular region containing varying numbers of cysteine-rich domains and an intracellular region that contains the death domain. The death receptors are activated in a ligand-dependent or independent manner and transduce apoptotic signals via their respective intracellular death domains. In addition to death receptors, several decoy molecules have also been identified and include DcR1/TRID, DcR2/TRUNDD, DcR3 and osteoprotegrin (OPG). The decoy molecules do not transduce apoptotic signals but rather compete with the death receptors for ligand binding and thereby inhibit ligand-induced apoptosis. Recent evidence suggests that p53 upregulates the expression of death receptors Fas and DR5, and thus, may mediate apoptosis in part via Fas and/or DR5. However, p53 also regulates the expression of TRAIL decoy receptors DcR1/TRID and DR2/TRUNDD. Although the significance of p53-dependent regulation of decoy receptors remains unclear, evidence suggests that DcR1/TRUNDD appears to inhibit 53-mediated apoptosis. It is, therefore, possible that p53 may blunt its DR5-dependent apoptotic effects by controlling the levels of decoy receptors.

The TRAIL decoy receptor TRUNDD (DcR2, TRAIL-R4) is induced by adenovirus-p53 overexpression and can delay TRAIL-, p53-, and KILLER/DR5-dependent colon cancer apoptosis.

The cell surface decoy receptor proteins TRID (also known as DcR1 or TRAIL-R3) and TRUNDD (DcR2, TRAIL-R4) inhibit caspase-dependent cell death induced by the cytotoxic ligand TRAIL in part because of their absent or truncated cytoplasmic death domains, respectively. We previously identified the death domain containing proapoptotic TRAIL death receptor KILLER/DR5 (TRAIL-R2) as an upregulated transcript following exposure of cancer cells, with wild-type but not with mutant or degraded p53 proteins, to a cytotoxic dose of adriamycin. In the present studies we provide evidence that expression of the TRAIL decoy receptors TRUNDD and TRID increases following infection of cancer cells with p53-expressing adenovirus (Ad-p53), in a manner similar to other p53 target genes such as KILLER/DR5 and p21WAF1/CIP1. Subsequent overexpression of TRUNDD in colon cancer cell lines caused a significant delay in killing induced by TRAIL. Furthermore, cotransfection of TRUNDD with either p53 or KILLER/DR5 (at a 4:1 DNA ratio) in colon cancer cells decreased cell death caused by either gene. This protective effect of TRUNDD was not dependent on the presence of TRAIL, and overexpression of TRUNDD did not alter the protein levels of either p53 or KILLER/ DR5. Further deletion studies showed that whereas protection by TRUNDD against TRAIL-mediated apoptosis did not require an intact intracellular domain (ICD), the first 43 amino acids of the ICD of TRUNDD were needed for protection against cell death induced by p53 or KILLER/DR5. Our results suggest a model in which the TRAIL decoy receptors may be induced by p53, thereby attenuating an apoptotic response that appears to involve KILLER/DR5. Therefore, the p53-dependent induction of TRUNDD may provide a mechanism to transiently favor cell survival over cell death, and overexpression of TRUNDD may be another mechanism of escape from p53-mediated apoptosis in gene therapy experiments.

Altered cell cycle control at the G(2)/M phases in aryl hydrocarbon receptor-null embryo fibroblast.

The aryl hydrocarbon receptor (AHR) is known to mediate the toxic and carcinogenic effects of polycyclic aromatic hydrocarbons and dioxins. High-affinity AHR ligands, such as 2,3,7, 8-tetrachlorodibenzeno-p-dioxin, have been shown to modify cell proliferation and differentiation. However, the mechanisms by which AHR affects cell proliferation and differentiation are not fully understood. To investigate the role of AHR in cell proliferation, mouse embryonic fibroblasts (MEFs) derived from AHR-null mice were obtained and characterized. Compared with wild-type MEFs, AHR-null cells exhibited a lower proliferation rate with an accumulation of 4N DNA content and increased apoptosis. The expression levels of Cdc2 and Plk, two kinases important for G(2)/M phase of cell cycle, were down-regulated in AHR-null MEFs. In contrast, transforming growth factor-beta (TGF-beta), a proliferation inhibitor in several cell lines, was present at high levels in conditioned medium from AHR-null MEFs. Concomitant with G(2)/M cell accumulation, treatment of wild-type MEFs with TGF-beta3 also resulted in down-regulation of both Cdc2 and Plk. Thus, overproduction of TGF-beta in AHR-deficient cells appears to be the primary factor that causes low proliferation rates and increased apoptosis. Taken together, these results suggest that AHR influences TGF-beta production, leading to an alteration in cell cycle control.

Transforming growth factor-beta 1 suppresses serum deprivation-induced death of A549 cells through differential effects on c-Jun and JNK activities.

Transforming growth factor (TGF)-beta1, a pleiotropic cytokine involved in regulating growth and differentiation, can exert both pro-apoptotic and anti-apoptotic effects depending on the cell type or circumstances. We observed that TGF-beta1 blocked apoptosis resulting from serum withdrawal in A549 human lung carcinoma cells. This was associated with suppression of JNK activation that occurs concomitant with the onset of apoptosis in the absence of TGF-beta1, suggesting that JNK plays an active role in the death process and that TGF-beta1 exerts its protective influence by altering JNK activity. Overexpression of a dominant negative mutant form of SEK1, an upstream activator of JNK, likewise suppressed JNK activation and inhibited apoptosis. Investigation of early events following TGF-beta1 treatment revealed an early induction and phosphorylation of c-Jun that was absent in cells subjected to serum withdrawal alone. That TGF-beta1-induced expression of c-Jun is important for survival was supported by the finding that overexpression of non-phosphosphorylatable dominant negative mutant c-Jun, c-Jun(S73A), attenuated the protective influence of TGF-beta1. Our findings suggest that JNK activation is a late but essential event in serum deprivation-induced apoptosis in A549 cells. TGF-beta1 prevents apoptosis, in part, through the early induction and phosphorylation of c-Jun, which in turn results in attenuated JNK activation.

Role of p53 family members in apoptosis.

p53-mediated apoptosis involves multiple mechanisms. A number of p53-regulated apoptosis-related genes have been identified. Some of these genes encode proteins that are important in controlling the integrity of mitochondria while the others code for membrane death receptors. p53 may also induce apoptosis by interfering with the growth factor-mediated survival signals. Although the transactivation-deficient p53 can induce apoptosis, evidence suggests that both the transcription-dependent and independent functions are needed for full apoptotic activity. p73 and p63 are two other members of the p53 family that show homology to p53 in their respective transactivation, DNA-binding and oligomerization domains. Both p73 and p63 transactivate p53-regulated promoters and induce apoptosis. Evidence suggests that both p73 and p63 may mediate apoptosis via some of the same mechanisms that are utilized by p53. However, both p73 and p63 exhibit features that are different from those of p53. Hence, both p73 and p63 are predicted to mediate apoptosis via mechanisms that are completely distinct from those engaged by p53. J. Cell. Physiol. 182:171-181, 2000. Published 2000 Wiley-Liss, Inc.

Role of Gadd45 in apoptosis.

gadd45 is a p53-regulated growth arrest and DNA-damage-inducible gene that is also regulated in a p53-independent manner. Whether Gadd45 plays a direct role in apoptosis remains unclear. Microinjection of the exogenous gadd45 expression vector into human fibroblasts has been shown to cause G2 arrest but not apoptosis. Recent studies suggest that Gadd45 may mediate genotoxic stress or Brca1-induced apoptosis via activation of c-Jun N-terminal kinase (JNK) and/or p38 mitogen-activated protein kinase (MAPK). Analyses of gadd45-deficient mice and cells have revealed that Gadd45 appears to exhibit pleiotropic effects, including cell cycle arrest at G2/M, DNA damage repair, and control of genomic stability, but is not required for radiation-induced apoptosis. Furthermore, stress-induced activation of JNK and p38 MAPK is not altered in gadd45-deficient embryonic fibroblasts, suggesting that the lack of Gadd45 may not affect the JNK and p38 MAPK activity. Thus, although the evidence from gadd45-null cells suggests that Gadd45 probably does not play a direct role in genotoxic stress-induced apoptosis, more in-depth studies are needed to firmly establish this contention.