Biomedical subjects

H Ouyang

Publications and source records attributed to H Ouyang.

At least 37 records · Page 2Linked to original sources

PubMed2000

Response of immortalized murine cementoblasts/periodontal ligament cells to parathyroid hormone and parathyroid hormone-related protein in vitro.

Cementum is an essential component of the periodontium, but the mechanisms involved in regulating the activity of this tissue are poorly understood. As one approach to better defining the cellular and molecular properties of cementum and the associated ligament, immortalized murine cell populations expressing gene markers associated with both cementoblasts (CM) and periodontal ligament cells (PDL), termed CM/PDL cells, were established. To further characterize these cells, their responsiveness to parathyroid hormone (PTH) and parathyroid hormone-related protein (PTHrP) was examined. CM/PDL cells were tested for the presence of steady state PTH-1 receptor mRNA using Northern blot analysis. In addition, the ability of PTH and PTHrP to stimulate cAMP production and c-fos mRNA expression in CM/PDL cells was determined, using a cAMP-binding assay and northern blot hybridization, respectively. Rat osteosarcoma cells (ROS 17/2.8) were used as a positive control and human periodontal ligament cells as a negative control. Northern blot analysis demonstrated that cells within the CM/PDL cell population expressed PTH-1 receptor mRNA. Both PTH (1-34) and PTHrP (1-34) increased cAMP and c-fos mRNA in CM/PDL cells. Furthermore, PTHrP treatment for either 24 or 48 h downregulated expression of transcripts for bone sialoprotein, osteocalcin and PTH-1 receptor by CM/PDL cells and abolished CM/PDL cell-mediated mineralization in vitro. These results indicate that cells within the CM/PDL population are targets for PTH and PTHrP action and that PTHrP may play an important part in regulating the biomineralization of cementum.

Animals↗

PubMed2000

Parathyroid hormone-related protein down-regulates bone sialoprotein gene expression in cementoblasts: role of the protein kinase A pathway.

PTH-related protein (PTHrP) acts as a paracrine and/or autocrine regulator of cell proliferation, apoptosis, and differentiation and is implicated in tooth development. The current studies employed cementoblasts to determine the role(s) and mechanisms of PTHrP in regulating cementum formation. Results demonstrated that PTHrP repressed gene expression and protein synthesis of bone sialoprotein (BSP) and abolished cementoblast-mediated biomineralization in vitro. The BSP gene inhibition required protein synthesis. The PTHrP analog (1-31) and other activators of the PKA pathway (3-isobutyl-1-methylxathine (IBMX), forskolin (FSK) and Sp-Adenosine-3', 5'-cyclic monophosphorothioate (Sp-cAMPss) also down-regulated BSP gene expression and blocked cementoblast-mediated biomineralization. In contrast, the PTHrP analog (7-34), a PTHrP antagonist, and the activators of the PKC pathway [phorbol 12-myristate 13-acetate (PMA) and phorbol 12, 13-dibutyrate (PDBu)] promoted BSP gene expression. In addition, the PKA pathway inhibitor (9-(2-tetrahydrofuryl) adenine (THFA) partially, but significantly reversed the PTHrP-mediated down-regulation of BSP gene expression. Furthermore, THFA alone significantly increased BSP messenger RNA (mRNA) expression in cementoblasts. In contrast, the inhibitor of the PKC pathway (GF109203X) did not reverse the PTHrP inhibitory effect on BSP gene expression. Furthermore, GF109203X alone dramatically reduced the BSP transcript levels. These data indicate that the cAMP/PKA pathway mediates the PTHrP-mediated down-regulation of BSP mRNA expression in cementoblasts; and furthermore, this pathway may, through an intrinsic inhibition mechanism, regulate the basal level of BSP mRNA expression. In contrast, the activation of PKC promotes BSP gene expression. These data provide new insights into the molecular mechanisms involved in PTHrP regulation of cementogenesis.

1-Methyl-3-isobutylxanthine↗

PubMed2000

Parathyroid hormone-related protein regulates extracellular matrix gene expression in cementoblasts and inhibits cementoblast-mediated mineralization in vitro.

Parathyroid hormone-related protein (PTHrP) has been implicated in regulating tooth eruption and/or development. Formation of cementum, a mineralized tissue covering the tooth root surface, is a critical biological event for tooth root development. To test the hypothesis that PTHrP targets cementoblasts (CMs) and acts to regulate cementogenesis, CM cell lines were established and their responsiveness to PTHrP stimulation was determined, in vitro. First, subclones were derived from two immortalized murine cell populations that contained CMs; SV-CM/periodontal ligament (PDL) cells were obtained from the root surface of first mandibular molars of CD-1 mice and immortalized with SV40 T-antigen (TAg), and OC-CM cell population was established from OC-TAg transgenic mice in which their cells harbor an osteocalcin (OC and/or OCN) promoter-driving immortal gene SV40 TAg. Based on our previous in situ studies, CM subclones were identified as cells expressing bone sialoprotein (BSP) and OCN transcripts, while PDL cell lines were designated as cells lacking BSP and OCN messenger RNA (mRNA). CMs exhibited a cuboidal appearance and promoted biomineralization, both in vitro and in vivo. In contrast, PDL cells (PDL subclones) displayed a spindle-shaped morphology and lacked the ability to promote mineralized nodule formation, both in vitro and in vivo. Next, using these subclones, the effect of PTHrP on cementogenesis was studied. CMs, not PDL cells, expressed PTH/PTHrP receptor mRNA and exhibited PTHrP-mediated elevation in cyclic adenosine monophosphate (cAMP) levels and c-fos gene induction. PTHrP stimulation repressed mRNA expression of BSP and OCN in CMs and blocked CM-mediated mineralization, in vitro. Collectively, these data suggest that CMs possess PTH/PTHrP receptors and, thus, are direct targets for PTHrP action during cementogenesis and that PTHrP may serve as an important regulator of cementogenesis.

Animals↗

PubMed2000

Employing a transgenic animal model to obtain cementoblasts in vitro.

BACKGROUND: Proper formation of cementum, a mineralized tissue lining the tooth root surface, is required for development of a functional periodontal ligament. Further, the presence of healthy cementum is considered to be an important criterion for predictable restoration of periodontal tissues lost as a consequence of disease. Despite the significance of cementum to general oral health, the mechanisms controlling development and regeneration of this tissue are not well understood and research has been hampered by the lack of adequate in vitro experimental models. METHODS: In an effort to establish cementoblast cell populations, without the trappings of a heterogeneous population containing periodontal ligament (PDL) cells, cells were obtained from the root surface of first mandibular molars of OC-TAg transgenic mice. These mice contain the SV40 large T-antigen (TAg) under control of the osteocalcin (OC) promoter. Therefore, only cells that express OC also express TAg and are immortalized in vitro. Based on results of prior in situ studies, OC is expressed by cementoblasts during root development, but not by cells within the PDL. Consequently, when populations are isolated from developing molars using collagenase/trypsin digestion, only cementoblasts, not PDL cells, are immortalized and thus, will survive in culture. RESULTS: The resulting immortalized cementoblast population (OC/CM) expressed bone sialoprotein (BSP), osteopontin (OPN), and OC, markers selective to cells lining the root surface. These cells also expressed type I and XII collagen and type I PTH/PTHrP receptor (PTH1R). In addition to expression of genes associated with cementoblasts, OC/CM cells promoted mineral nodule formation and exhibited a PTHrP mediated cAMP response. CONCLUSIONS: This approach for establishing cementoblasts in vitro provides a model to study cementogenesis as required to enhance our knowledge of the mechanisms controlling development, maintenance, and regeneration of periodontal tissues.

Animals↗

PubMed2000

Analysis of the candidate target genes for mutation in microsatellite instability-positive cancers of the colorectum, stomach, and endometrium.

Microsatellite instability (MSI) in human carcinoma DNA is a characteristic phenotype observed in hereditary non-polyposis colorectal cancer and also in some human sporadic cancers including multiple primary carcinomas. In this study, we analyzed mutations in the hCHK1, E2F4, hMSH3, and hMSH6 genes in MSI+ human cancers arising in colorectum, stomach and endometrium. The E2F4 and hMSH3 genes were mutated in all tumor types. Interestingly, the hMSH6 gene was mutated in colorectal and gastric cancers but not in endometrial cancer; this is similar to the TGFbetaRII gene. It is notable that the mutation status of the secondary mutators, hMSH3 and hMSH6, did not influence slippage-related frameshift mutations in genes harboring simple tandem-repeats, which suggests that the MSI phenotype may be affected mainly by abnormalities in the primary mutator genes, not by the secondary mutator genes. No mutations were observed in the cell cycle checkpoint gene hCHK1; mutations of this gene are thought to have a limited role, if any, in at least the tumor types analyzed in this study.

Checkpoint Kinase 1↗

PubMed2000

[Impacts of forest and precipitation on runoff and sediment in Tianshui watershed and GM models].

This paper analyzed the impacts of foret stand volume and precipitation on annual erosion modulus, mean sediment, maximum sediment, mean runoff, maximum runoff, minimum runoff, mean water level, maximum water level and minimum water level in Tianshui watershed, and also analyzed the effect of the variation of forest stand volume on monthly mean runoff, minimum runoff and mean water level. The dynamic models of grey system GM(1, N) were constructed to simulate the changes of these hydrological elements. The dynamic GM models on the impact of stand volumes of different forest types(Chinese fir, masson pine and broad-leaved forests) with different age classes(young, middle-aged, mature and over-mature) and that of precipitation on the hydrological elements were also constructed, and their changes with time were analyzed.

Chemical Precipitation↗

PubMed1999

DNA-dependent protein kinase-independent activation of p53 in response to DNA damage.

Phosphorylation at serine 15 of the human p53 tumor suppressor protein is induced by DNA damage and correlates with accumulation of p53 and its activation as a transcription factor. The DNA-dependent protein kinase (DNA-PK) can phosphorylate serine 15 of human p53 and the homologous serine 18 of murine p53 in vitro. Contradictory reports exist about the requirement for DNA-PK in vivo for p53 activation and cell cycle arrest in response to ionizing radiation. While primary SCID (severe combined immunodeficiency) cells, that have defective DNA-PK, show normal p53 activation and cell cycle arrest, a transcriptionally inert form of p53 is induced in the SCID cell line SCGR11. In order to unambiguously define the role of the DNA-PK catalytic subunit (DNA-PKcs) in p53 activation, we examined p53 phosphorylation in mouse embryonic fibroblasts (MEFs) from DNA-PKcs-null mice. We found a similar pattern of serine 18 phosphorylation and accumulation of p53 in response to irradiation in both control and DNA-PKcs-null MEFs. The induced p53 was capable of sequence-specific DNA binding even in the absence of DNA-PKcs. Transactivation of the cyclin-dependent-kinase inhibitor p21, a downstream target of p53, and the G1 cell cycle checkpoint were also found to be normal in the DNA-PKcs -/- MEFs. Our results demonstrate that DNA-PKcs, unlike the related ATM protein, is not essential for the activation of p53 and G1 cell cycle arrest in response to ionizing radiation.

Animals↗

PubMed1999

Surface exposure of the methionine side chains of calmodulin in solution. A nitroxide spin label and two-dimensional NMR study.

Binding of calcium to calmodulin (CaM) causes a conformational change in this ubiquitous calcium regulatory protein that allows the activation of many target proteins. Met residues make up a large portion of its hydrophobic target binding surfaces. In this work, we have studied the surface exposure of the Met residues in the apo- and calcium-bound states of CaM in solution. Complexes of calcium-CaM with synthetic peptides derived from the CaM-binding domains of myosin light chain kinase, constitutive nitric-oxide synthase, and CaM-dependent protein kinase I were also studied. The surface exposure was measured by NMR by studying the effects of the soluble nitroxide spin label, 4-hydroxyl-2,2,6, 6-tetramethylpiperidinyl-1-oxy, on the line widths and relaxation rates of the Met methyl resonances in samples of biosynthetically 13C-methyl-Met-labeled CaM. The Met residues move from an almost completely buried state in apo-CaM to an essentially fully exposed state in Ca2+4-CaM. Binding of two Ca2+ to the C-terminal lobe of CaM causes full exposure of the C-terminal Met residues and a partial exposure of the N-terminal Met side chains. Binding of the three target peptides blocks the access of the nitroxide surface probe to nearly all Met residues, although the mode of binding is distinct for the three peptides studied. These data show that calcium binding to CaM controls the surface exposure of the Met residues, thereby providing the switch for target protein binding.

Animals↗

PubMed1999

Catalytic subunit of DNA-dependent protein kinase: impact on lymphocyte development and tumorigenesis.

The DNA-dependent protein kinase (DNA-PK) consists of a heterodimer DNA-binding complex, Ku70 and Ku80, and a large catalytic subunit, DNA-PKcs. To examine the role of DNA-PKcs in lymphocyte development, radiation sensitivity, and tumorigenesis, we disrupted the mouse DNA-PKcs by homologous recombination. DNA-PKcs-null mice exhibit neither growth retardation nor a high frequency of T cell lymphoma development, but show severe immunodeficiency and radiation hypersensitivity. In contrast to the Ku70-/- and Ku80-/- phenotype, DNA-PKcs-null mice are blocked for V(D)J coding but not for signal-end joint formation. Furthermore, inactivation of DNA-PKcs leads to hyperplasia and dysplasia of the intestinal mucosa and production of aberrant crypt foci, suggesting a novel role of DNA-PKcs in tumor suppression.

Animals↗

PubMed1999

Immortalized cementoblasts and periodontal ligament cells in culture.

Cementum, a mineralized tissue lining the surface of the tooth root, is required for formation of a functional periodontal ligament attachment during development. Additionally, during regeneration of tissues after disease, cementum is thought to play a critical role in the reparative process. Research efforts aimed toward understanding mechanisms involved in periodontal development and regeneration, and in particular the formation of root cementum, have been hampered by an inability to isolate and culture cells involved in cementum production, i.e., cementoblasts. Using classical techniques for osteoblast isolation, immortalized, heterogeneous cementoblast/periodontal ligament cell (CM/PDL) populations were established from cells lining the tooth root surface of: 1) CD-1 mice, where cells were immortalized using SV40, or 2) H-2KbtsA58 "immorto" mice, where cells containing an immortalizing transgene were removed and cultured. CM/PDL populations were derived from tissues adherent to developing tooth root surfaces, while tissues adherent to the surrounding alveolar bone were specifically excluded from the population. Immortalized CM/PDL cells were characterized to ensure their phenotype reflected that previously demonstrated in situ and in primary, nonimmortalized cultures. Proteins/mRNAs associated with bone/cementum and known to be expressed by root lining cementoblasts, but not by PDL cells, in situ, e.g., bone sialoprotein, osteopontin, and osteocalcin, were expressed by cells within the immortalized populations. Furthermore, CM/PDL cells, in vitro, attached to bone sialoprotein in an arginine-glycineaspartic acid (RGD)-dependent manner, promoted mineral nodule formation and exhibited a PTH/PTHrP-mediated cAMP response. These immortalized heterogeneous populations, containing both CM and PDL cells, provide a unique opportunity to study cells involved in cementogenesis and to enhance our knowledge of the mechanisms controlling development, maintenance, and regeneration of periodontal tissues.

Animals↗

PubMed1999

Identification of three commonly deleted regions on chromosome arm 6q in human pancreatic cancer.

Pancreatic cancer has one of the poorest prognoses among malignant diseases. To understand its molecular mechanisms, we studied allelic losses on the long arm of chromosome 6. Using 55 paired DNAs of tumors and their corresponding normal tissues and 30 microsatellite markers that spanned the entire 6q chromosome arm, we found three distinct regions of common allelic loss: region A, a less than 500-kb region bordered by D6S449 and D6S283 on 6q21 with a loss of heterozygosity (LOH) frequency of 69% (38/55); region B, a 7-cM region bordered by D6S292 and D6S308 on 6q23-q24 with a LOH frequency of 60% (33/55); and region C, a 13-cM region bordered by D6S305 and D6S264 with a LOH frequency of 51% (28/55). We further focused on region A and constructed a physical map using yeast artificial chromosome (YAC) clones, their derived cosmid clones, and bacterial artificial chromosome (BAC) clones. Region A was completely covered by three overlapping BAC clones. Our results in the present study should shed light on the cloning and characterization of tumor suppressor genes in pancreatic carcinogenesis.

Adult↗

PubMed1998

Identification of two common regions of allelic loss in chromosome arm 12q in human pancreatic cancer.

Using the method of microsatellite analysis, we studied 40 tissues with pancreatic ductal adenocarcinoma and identified two commonly deleted regions on the long arm of chromosome 12. One (region A) was found between D12S81 and D12S1719 at 12q21 at a frequency of 67.5%, and the other (region B) was located between D12S360 and D12S78 at 12q22-q23.1 at a frequency of 60%; the latter was reported previously (M. Kimura, et al. Genes Chromosomes Cancer, 17: 88-93, 1996). The results of microsatellite analyses were verified by fluorescence in situ hybridization. We further analyzed 19 pancreatic cancer cell lines by fluorescence in situ hybridization and found that 10 of them showed allelic loss at D12S81 and 6 showed allelic loss at D12S360. Yeast artificial chromosome contigs were constructed to cover the deleted regions. Region B was completely covered by a 650-kb yeast artificial chromosome clone. The frequently deleted regions in chromosome 12q in pancreatic cancer that were identified here may provide new avenues for isolating novel tumor suppressor genes.

Adult↗

PubMed1998

Melatonin and serotonin interactions with calmodulin: NMR, spectroscopic and biochemical studies.

It has been reported that the hormone melatonin binds tightly to the ubiquitous calcium-regulatory protein, calmodulin (CaM) with a Kd value around 0.1 nM [Benítez-King et al., Biochim. Biophys. Acta, 1290 (1993) 191-196]. Normally CaM only binds to target proteins and various 20-residue synthetic peptides encompassing the CaM-binding domain of these target proteins with K(d) values ranging between 1.0 microM and 0.1 nM. Here we have studied the interaction of melatonin and several structurally related compounds--serotonin, 5-hydroxytryptophan, and tryptophan--to CaM through gel band shift assays, enzymatic competition assays with calcineurin, fluorescence spectroscopy, far and near UV circular dichroism spectropolarimetry and NMR spectroscopy. Fluorescence spectra show that the binding is calcium dependent. NMR studies with biosynthetically labelled methyl-13C-Met CaM show that melatonin and the other compounds interact with the hydrophobic cleft regions of the protein. Our NMR data show that melatonin binds to both domains of the dumbbell-shaped CaM, while serotonin appears to bind only to the C-terminal domain. This binding mode is further substantiated by fluorescence and gel band shift competition experiments with synthetic peptides from myosin light chain kinase and constitutive nitric oxide synthase. Circular dichroism spectra indicate that the secondary structure of CaM is not altered by addition of melatonin. Our data are internally consistent and reveal Kd values in the mM range for melatonin. Thus the binding of these compounds to CaM is substantially weaker than was previously reported and is unlikely to be of physiological significance.

Binding, Competitive↗

PubMed1998

Ku70: a candidate tumor suppressor gene for murine T cell lymphoma.

We present evidence that inactivation of the Ku70 gene leads to a propensity for malignant transformation both in vitro and in vivo. In vitro, Ku70-/- mouse fibroblasts displayed an increased rate of sister chromatid exchange and a high frequency of spontaneous neoplastic transformation. In vivo, Ku70-/- mice, known to be defective in B but not T lymphocyte maturation, developed thymic and disseminated T cell lymphomas at a mean age of 6 months with CD4+CD8+ tumor cells. These findings directly demonstrate that Ku70 deficiency facilitates neoplastic growth and suggest a novel role of the Ku70 locus in tumor suppression.

Animals↗

PubMed1998

Metal ion binding to calmodulin: NMR and fluorescence studies.

Calmodulin is an important second messenger protein which is involved in a large variety of cellular pathways. Calmodulin is sensitive to fluctuations in the intracellular Ca2+ levels and is activated by the binding of four Ca2+ ions. In spite of the important role it plays in signal transduction pathways, it shows a surprisingly broad specificity for binding metal ions. Using 15N-Gly biosynthetically-labelled calmodulin, we have studied the binding of different metal ions to calmodulin, including K+, Na+, Ca2+, Mg2+, Zn2+, Cd2+, Pb2+, Hg2+, Sr2+, La3+ and Lu3+, by 1H,15N HMQC NMR experiments. The effects of these ions on the substrate-binding ability of calmodulin have also been studied by fluorescence spectroscopy of the single tryptophan residue in a 22-residue synthetic peptide encompassing the skeletal muscle myosin light chain kinase calmodulin-binding domain. Most of these metal ions can activate a calmodulin target enzyme to some extent, though they bind to calmodulin in a different manner. Mg2+, which is of direct physiological interest, has a distinct site-preference for calmodulin, as it shows the highest affinity for site I in the N-terminal domain, while the C-terminal sites III and IV are the high affinity binding sites for Ca2+ (as well as for Cd2+). At a high concentration of Mg2+ and a low concentration of Ca2+, calmodulin can bind Mg2+ in its N-terminal lobe while the C-terminal domain is occupied by Ca2+; this species could exist in resting cells in which the Mg2+ level significantly exceeds that of Ca2+. Moreover, our data suggest that the toxicity of Pb(2+)--which, like Sr2+, binds with an equal and high affinity to all four sites--may be related to its capacity to tightly bind and improperly activate calmodulin.

Amino Acid Sequence↗

PubMed1998

Isolation of murine cementoblasts: unique cells or uniquely-positioned osteoblasts?

While cementoblasts express a number of mineral-related proteins, including bone sialoprotein (BSP), osteopontin (OPN) and osteocalcin (OC), these proteins do not appear to be expressed by cells of the intermediate dental follicle/periodontal ligament (PDL). This information was utilized in an experimental strategy to isolate presumptive cementoblasts from the root surface of day 24 murine mandibular first molars. Using microscopic dissection techniques, molars were carefully extracted from their alveolar crypts and subjected to trypsin-collagenase digestion to remove adherent cells. Primary cultures were established and assayed for expression of proteins known to be expressed by cementoblasts at this timepoint in vivo (i.e. BSP, OPN, OC) and also an odontoblast-specific protein (i.e. DSP) to rule out contamination by pulpal cells. A subgroup of cells were found to express Type I collagen (89% of cells), BSP (46%), OPN (23%) and OC (30%); DSP was not detected within these cultures. We propose that cells within this heterogeneous population, which express this profile of osteogenic proteins, represent cementoblasts. The availability of a cementoblast cell line will make possible rigorous and controlled in vitro analysis of these cells and allow for determination of the unique characteristics of these cells not shared with other cells, particularly osteoblasts.

Animals↗

PubMed1998

[Imaging manifestations of tumors metastasized in fatty liver].

OBJECTIVE: To evaluate the manifestations of tumors metastasized in fatty liver and the value of various imaging modalities, especially CT. METHODS: Nine cases of tumors metastasized in fatty liver were proved by clinical follow-up for 3-13 months. The primary neoplasms were breast carcinoma in 6 cases; ovarian carcinoma, malignant melanoma and colon carcinoma, one case for each. All had CT(19 episodes) and ultrasonography (US, 20 episodes). Four cases had MRI and 2 cases had DSA. RESULTS: Liver metastatic lesions were missed by US in 2 cases with moderate to marked fatty liver. On CT without contrast administrations, fatty liver was divided into marked, moderate and mild degree according to the density of hepatic parenchyma which was lower than that of the spleen; lower and higher than or equal to that of the intrahepatic blood vessels. Depending on the degree of fat infiltration(FI), the density of the metastatic lesions was high when FI was marked and low when FI was mild. However, when FI was moderate, the density of the metastatic lesions varied, being high, equal or low. On enhanced CT, all of the lesions were enhanced with moderate to marked fatty liver background. Lesions were heterogeneous in 4 cases. On plain CT, metastatic lesions had high-density rim, 2-6 mm in width in 4 cases. In SE sequence of MRI, metastatic lesions were hypointense on T1W and hyperintense on T2W, and moderately hyperintense on opposed-phase. CONCLUSION: Tumors metastasized in fatty liver show a broad spectrum of image manifestations. They are related to the degree of fat infiltration. On plain CT, isodense lesions are easily escaped detection when moderate degree of fatty liver is present. Contrast administrations is mandatory. Liver metastases is suggested if a lesion is found with hyperattenuating rim on plain CT, or appears heterogeneous after enhancement. MRI is of diagnostic help.

Adult↗

PubMed1998

The BAX gene, the promoter of apoptosis, is mutated in genetically unstable cancers of the colorectum, stomach, and endometrium.

Disruption of the DNA mismatch repair system, characterized by microsatellite instability (MI), plays an important role in the course of human carcinogenesis by increasing the rate of mutations of genes associated with cancers. However, it is not clear which genes are the target genes for mutation in the course of carcinogenesis. Microsatellites within the coding region of the transforming growth factor beta receptor type II (RII) and insulin-like growth factor II receptor (IGF-IIR) genes were reported to be targets for mutation during the course of carcinogenesis in MI+ tumors. Recently, somatic mutations were found in a poly(G)8 tract in the BCL-2-associated X protein (BAX) gene, one of the essential players in apoptosis, in some MI+ tumors. We examined mutations of BAX in MI+ cancers of various organs and found frameshift mutations at the poly(G)8 tract in 5 of 15 (33%) gastric cancers, 3 of 26 (12%) endometrial cancers, and 9 of 22 (41 %) colorectal cancers. In contrast, no such mutations were found in pancreatic cancer. These results suggest that mutations of BAX play an important role in the course of carcinogenesis in the stomach, colorectum, and endometrium.

Apoptosis↗