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A Ristimäki

Publications and source records attributed to A Ristimäki.

At least 19 recordsLinked to original sources
PubMed2006

A heparan sulfate-targeted conditionally replicative adenovirus, Ad5.pk7-Delta24, for the treatment of advanced breast cancer.

Conditionally replicating adenoviruses (CRAds) that replicate in tumor but less in normal cells are promising anticancer agents. A major determinant of their potency is their capacity for infecting target cells. The primary receptor for serotype 5 adenovirus (Ad5), the most widely used serotype in gene therapy, is the coxsackie-adenovirus receptor (CAR). CAR is expressed variably and often at low levels in various tumor types including advanced breast cancer. We generated a novel p16/retinoblastoma pathway-dependent CRAd, Ad5.pK7-Delta24, with a polylysine motif in the fiber C-terminus, enabling CAR-independent binding to heparan sulfate proteoglycans (HSPG). Ad5.pK7-Delta24 mediated effective oncolysis of all breast cancer cell lines tested. Further, we utilized noninvasive, fluorescent imaging for analysis of antitumor efficacy in an orthotopic model of advanced hormone refractory breast cancer. A therapeutic benefit was seen following both intratumoral and intravenous delivery. Murine biodistribution similar to Ad5, proven safe in trials, suggests feasibility of clinical safety testing. Interestingly, upregulation of CAR was seen in low-CAR M4A4-LM3 breast cancer cells in vivo, which resulted in better than expected efficacy also with an isogenic CRAd with an unmodified capsid. These results suggest utility of Ad5.pK7-Delta24 and the orthotopic model for further translational studies.

Adenoviridae↗
PubMed2006

Cyclooxygenase-2 expression correlates with poor prognosis in pancreatic cancer.

BACKGROUND: Cyclooxygenase-2 (COX-2) overexpression is related to poor outcome in several cancers. COX-2 is upregulated in 42-90% of pancreatic ductal adenocarcinomas and is a potential target for chemotherapy. Earlier studies have not shown the expression of COX-2 to be a prognostic factor in pancreatic cancer. OBJECTIVE: To evaluate the prognostic value of COX-2 in a series of patients with pancreatic adenocarcinoma. METHODS: 128 patients operated on for pancreatic adenocarcinoma at Helsinki University Central Hospital between 1974 and 1998 provided sections from primary tumours which were immunohistochemically stained with a COX-2-antihuman monoclonal antibody. RESULTS: Cytoplasmic COX-2 reactivity (>5%) occurred in 46 specimens (36%), correlating neither with age, sex, stage, size, tumour stage, nodal metastases, nor grade. Lack of COX-2 expression correlated with distant metastases (p = 0.026). In univariate survival analysis, COX-2 expression (p = 0.0114), stage (p = 0.0002), grade (p = 0.0001), and age (p = 0.042) had prognostic significance. One, two, and five year survival rates were 51%, 32%, and 8% in the COX-2 negative groups compared with 34%, 5%, and 5% in the COX-2 positive groups (p = 0.011). Prognostic significance was especially high for patients operated on with curative intent (p = 0.004). In multivariate analysis, COX-2 was an independent prognostic factor (hazard ratio = 1.6 (95% confidence interval, 1.1 to 2.3)). CONCLUSIONS: Expression of COX-2 was associated with poor outcome from pancreatic ductal adenocarcinoma and was independent of tumour stage, grade, or age in multivariate analysis.

Adenocarcinoma↗
PubMed2006

Decreased xanthine oxidoreductase is a predictor of poor prognosis in early-stage gastric cancer.

BACKGROUND: Xanthine oxidoreductase (XOR) is a key enzyme in the degradation of DNA, RNA and high-energy phosphates. About half of the patients with breast cancer have a decrease in XOR expression. Patients with breast cancer with unfavourable prognosis are independently identified by the loss of XOR. AIM: To assess the clinical relevance of XOR expression in gastric cancer. METHODS: XOR levels were studied by immunohistochemistry in tissue microarray specimens of 337 patients with gastric cancer and the relation between XOR expression and a series of clinicopathological variables, as well as disease-specific survival, was assessed. RESULTS: XOR was moderately decreased in 41% and was undetectable in another 14% of the tumours compared with the corresponding normal tissue. Decreased XOR was associated with advanced stage, deep tumour penetration, diffusely spread tumour location, positive lymph node status, large tumour size, non-curative disease, cellular aneuploidy, high S-phase fraction and high cyclooxygenase-2 expression, but not with p53 expression or Borrmann classification. Down regulation of XOR was associated with unfavourable outcome, and the cumulative 5-year gastric cancer-specific survival in patients with strong XOR expression was 47%, compared with 22% in those with moderate to negative expression (p<0.001). This was also true in patients with stage I-II (p = 0.01) and lymph node-negative (p = 0.02) disease, as well as in patients with smaller (< or =5 cm) tumours (p = 0.02). CONCLUSION: XOR expression in gastric cancer may be a new marker for a more aggressive gastric cancer biology, similar to that previously reported for breast cancer.

Adenocarcinoma↗
PubMed2006

MMP-2 but not MMP-9 associated with COX-2 and survival in gastric cancer.

BACKGROUND AND AIM: Matrix metalloproteinases (MMPs) MMP-2 and MMP-9 can degrade type IV collagen of extracellular matrix and basal membranes. As cyclo-oxygenase-2 (COX-2) has been shown to activate MMPs, creating one of the COX-2-promoted pathways of tumour growth and metastasis, the prognostic role of MMP-2 and MMP-9 in gastric cancer was assessed and their association with COX-2 expression was evaluated. MATERIALS AND METHODS: Samples were collected from 342 consecutive patients operated on for gastric cancer, of which 315 were acceptable for MMP-2, MMP-9 and COX-2 immunohistochemistry. Specimens were stained with specific antibodies, evaluated and categorised by two interpreters, and then correlated with clinical data and survival. RESULTS: Epithelial MMP-2 immunoreactivity was associated with male sex, high stage, advanced penetration depth, non-curative surgery, high COX-2 expression and poor survival. Stromal MMP-2 expression correlated with high stage, intestinal type and non-curative surgery whereas MMP-9 correlated only with intestinal type. Stage, intent of surgery and COX-2 were independent prognostic factors. CONCLUSIONS: Epithelial MMP-2 expression in gastric cancer is associated with aggressive forms, COX-2 and poor survival, although MMP-2 was not an independent prognostic factor. In gastric cancer tumour growth is apparently induced by COX-2, and invasion is mediated by MMP-2.

Adenocarcinoma↗
PubMed2004

Cell-cell contacts trigger programmed necrosis and induce cyclooxygenase-2 expression.

Necrosis was induced by cell-cell contacts of human dermal fibroblasts in three-dimensional culture. Dramatic induction of cyclooxygenase-2 (COX-2) expression was found throughout these necrotizing cell clusters, whereas no increase in expression of apoptosis markers was seen. The cells were rapidly committed to necrosis, and the process could not be reversed by allowing them to spread and adhere on a solid substrate. Induction of COX-2 expression was accompanied by greatly enhanced production of the prostaglandins E(2), I(2), and F(2alpha). When applied exogenously on necrotizing clusters, these prostaglandins delayed cell clustering and further enhanced COX-2 expression. Abolishing prostaglandin production by NS-398 or indomethacin reduced cell membrane damage (as measured by lactate dehydrogenase release into the culture medium). We also identified alpha-enolase-mediated plasminogen activation as the major extracellular proteolytic executor of necrotic cell death. In contrast to inhibition of COX-2, inhibition of plasminogen activation failed to inhibit membrane damage associated with necrosis. Intracellular proteolysis, by caspases, was shown to take part in COX-2 induction. Taken together, our results indicate that cell-cell contacts induce an actively programmed necrotic process that functionally involves COX-2, a known hallmark of inflammation and cancer.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2004

Expression of COX-2 is increased with age in papillary thyroid cancer.

AIMS: To study cyclooxygenase-2 (COX-2) and matrix metalloproteinase-2 (MMP-2) expression in papillary thyroid cancer (PTC). Expression of COX-2 is elevated in various human tumours and it has an important role in carcinogenesis. MMP-2 is also an important component of the metastatic potential of tumours. In PTC the most important factor affecting survival is age, but it is poorly understood why older PTC patients have a worse prognosis. METHODS AND RESULTS: This retrospective study comprised 108 patients with PTC, and we compared patients who were either younger than 35 (n = 59) or older than 55 (n = 49). Paraffin-embedded tumour samples were analysed for COX-2 and MMP-2 protein expression using immunohistochemistry. High (scores 2-3) COX-2 immunostaining was observed in 38/108 (35%) of the tumours, and COX-2 expression was significantly (P = 0.002) higher in the older age group (25/49; 51%) than in the young one (13/59; 22%). CONCLUSIONS: Our study shows that COX-2 expression increases with age. It is possible that the age-related increase in COX-2 expression could explain the more aggressive behaviour of PTC in the older age group compared with the young one.

Adult↗
PubMed2003

DNA copy number changes in young gastric cancer patients with special reference to chromosome 19.

Only a few cytogenetic and genetic studies have been performed in gastric cancer patients in young age groups. In the present study we used the comparative genomic hybridisation (CGH) method to characterise frequent DNA copy number changes in 22 gastric cancer patients of 45 years or younger and three gastric cancer cell lines established from patients younger than 45 years. Analysis of DNA copy number changes revealed frequent DNA copy number increases at chromosomes 17q (52%), 19q (68%) and 20q (64%). To confirm the CGH results and to characterise the amplicon region on the most frequently amplified chromosome, chromosome 19, we carried out fluorescence in situ hybridisation (FISH) analysis and Southern blot analysis. Fluorescence in situ hybridisation with the bacterial artificial chromosome (BAC) clone mapped to 19q12 indicated a copy number increase in all eight tumour specimens studied. Southern blot analysis of six tumour specimens and three tumour cell lines, with five probes mapped to the 19q12-13.2 region, suggested cyclin E to be one of the candidate target genes in the 19q region for gastric cancer tumorigenesis. Cyclin E protein overexpression was verified in tumours with amplification on chromosome 19. Further studies are required to investigate the biological and clinical significance of 19q amplicon and cyclin E upregulation in gastric cancer of young patients.

Adolescent↗
PubMed2003

COX-2 expression in striated muscle under physiological conditions.

OBJECTIVES: The role of cyclooxygenase-2 (COX-2) in disease has been extensively studied, (Annu Rev Med (2002) 53:35; N Engl J Med (2001) 345:433) but less information is available with respect to possible physiological functions of COX-2. Information on how and where COX-2 is expressed under physiological conditions may increase our understanding of its physiological role. Previous studies have revealed a COX-2 dependent production of prostanoids under physiological conditions, without entirely determining the source of this production. MATERIALS AND METHODS: To assess COX-2 expression under normal conditions, we analyzed tissue specimens that were removed from 30 healthy study subjects in conjunction with surgical procedure related to insertion of dental implants and from three patients which had muscle tissue from Quadriceps femoris muscle removed as part of surgical treatment of soft tissue sarcomas not directly affecting the muscle tissue. Immunohistochemistry and immunoblotting (Western blotting) was used to assess the presence of COX-2 protein. RESULTS: In 25 of 30 patients (83%), COX-2 protein was expressed in striated muscle, as assessed by immunohistochemistry. All cases had COX-2 expression verified by Western blotting. In none of the 25 subjects with COX-2 expression did we notice concomitant inflammation of the adjacent submucosal tissue. CONCLUSIONS: It is a novel finding that COX-2 is expressed in striated muscle under physiological conditions. COX-2 activity in striated muscle is a possible explanation for the hitherto unknown localization of prostanoids synthesis under physiological conditions.

Adolescent↗
PubMed2003

Role of cyclooxygenase-2 in the development and treatment of oesophageal adenocarcinoma.

BACKGROUND: Various studies suggest that aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) are promising anticancer agents. Epidemiological studies have found that long-term use of NSAIDs is associated with a reduced incidence of colorectal, gastric and oesophageal cancers, while experimental and clinical studies have demonstrated that treatment with NSAIDs causes a statistically significant reduction in both the number and the size of polyps in familial adenomatous polyposis (FAP) patients. METHODS: In this review, the mechanisms by which NSAIDs exert their chemopreventive and antineoplastic effects are described. RESULTS: Although the precise anticancer actions of NSAIDs are not fully explained, they probably involve inhibition of cyclooxygenase (COX), which is the rate-limiting enzyme in the conversion of arachidonic acid to prostaglandins. Two isoforms of this enzyme (COX-1 and COX-2) have been identified. COX-1 is constitutively expressed and considered to be a housekeeping gene, while COX-2 is not usually detectable in normal tissues, but can be readily induced in processes like inflammation, reproduction and carcinogenesis. The mechanisms by which COX-2 is thought to be involved in the carcinogenesis include resisting apoptosis, increasing cell proliferation, stimulating angiogenesis and modulating the invasive properties of cancer cells. CONCLUSION: This report reviews the mechanisms by which COX-2 can contribute to carcinogenesis, its role in prognosis, and the possible place of selective COX-2 inhibitors in the prevention and treatment of gastrointestinal malignancies, focusing particularly on oesophageal cancer.

Adenocarcinoma↗
PubMed2003

Comparison of cyclooxygenase 2 expression in adenocarcinomas of the gastric cardia and distal oesophagus.

BACKGROUND: Adenocarcinomas of the gastric cardia and distal oesophagus are at present often considered as one clinical entity because of their comparable increasing incidence, prognosis, and optimal treatment options. However, it is still a matter of debate whether these malignancies have the same pathogenesis and genotype. AIMS: The aim of this study was to analyse expression of cyclooxygenase 2 (COX-2) in cardia carcinomas, and correlate this expression with clinicopathological parameters and survival. The results were compared with the prognostic value of COX-2 found for Barrett carcinomas. METHODS: Tumour sections of 134 consecutive patients undergoing potentially curative surgery for an adenocarcinoma of the gastric cardia and substantially invading the distal oesophagus were immunohistochemically stained using a COX-2 monoclonal antibody. Specimens were blindly scored based on intensity and extent of COX-2 immunopositivity. RESULTS: COX-2 expression was negative to weak in 59% ("COX-2 low") and moderate to strong in 41% ("COX-2 high") of tumours. This was significantly lower than in Barrett carcinomas (p<0.0001). COX-2 expression was not correlated with any clinicopathological parameter. A correlation between elevated COX-2 expression and reduced survival, as described for Barrett carcinomas, was not identified for cardiac carcinomas. CONCLUSIONS: There is a difference in COX-2 expression with respect to intensity and prognostic significance between adenocarcinomas of the gastric cardia and distal oesophagus. This suggests a different pathogenesis and different genetic constitution of these two cancers. Based on these findings, the role of selective COX-2 inhibitors in the treatment of adenocarcinomas of the gastric cardia is less promising than in Barrett carcinomas.

Adenocarcinoma↗
PubMed2002

Expression of cyclooxygenase-2 in intestinal goblet cells of pre-diabetic NOD mice.

Cyclooxygenase, the rate-limiting enzyme in prostaglandin synthesis, is expressed in constitutive (COX-1) and inducible (COX-2) isoforms. The COX-2 has been proposed to be involved in development of autoimmune type 1 diabetes (T1D). We examined COX-2 expression in the gut-associated lymphoid tissue (GALT), and found COX-2 was strongly expressed in goblet cells of non-obese diabetic (NOD) mice at the apical villi at the age of 2.5 weeks, clearly before the onset of insulitis, while the expression in the control BALB/c mice was weak or absent at all ages (P < 0.001). Lipopolysaccharide (LPS) given intraperitoneally slightly increased COX-2 expression in the goblet cells and epithelium of both NOD and BALB/c mice. High-resolution confocal microscopy showed that the surroundings of the goblet cells contained no COX-2, implying that the enzyme is synthesized by the goblet cells. The COX-2 is secreted from goblet cells into the intestinal lumen along with mucins. The COX-2 concentration in the goblet cell of BALB/c and especially of NOD mice was markedly higher than that in the intraepithelial lymphocytes or lamina propria macrophages. High mucin COX-2 from goblet cells may increase luminal prostaglandin synthesis, alter epithelial permeability, modulate intestinal immune responses and modify functional properties of the lymphocytes in the GALT, which all may be important for the initiation of the autoimmune phenomenon in the NOD mice.

Animals↗
PubMed2001

Expression of cyclooxygenase-2 in human transitional cell carcinoma of the urinary bladder.

Recent studies suggest that expression of cyclooxygenase-2 (Cox-2) is elevated in transitional cell carcinoma (TCC) of the urinary bladder and that inhibition of Cox-2 activity suppresses bladder cancer in experimental animal models. We have investigated the expression of Cox-2 protein in human TCCs (n = 85), in in situ carcinomas (Tis) of the urinary bladder (n = 17), and in nonneoplastic urinary bladder samples (n = 16) using immunohistochemistry. Cox-2 immunoreactivity was detected in 66% (67 of 102) of the carcinomas, whereas only 25% (4 of 16) of the nonneoplastic samples were positive (P: < 0.005). Cox-2 immunoreactivity localized to neoplastic cells in the carcinoma samples. The rate of positivity was the same in invasive (T1-3; 70%, n = 40) and in noninvasive (Tis and Ta; 65%, n = 62) carcinomas, but noninvasive tumors had a higher frequency (32%) of homogenous pattern of staining (>90% of the tumor cells positive) than the invasive carcinomas (10%) (P: < 0.05). However, several invasive TCCs exhibited the strongest intensity of Cox-2 staining in the invading cells, whereas other parts of the tumor were virtually negative. Finally, strong Cox-2 positivity was also found in nonneoplastic ulcerations (2 of 2) and in inflammatory pseudotumors (2 of 2), in which the immunoreactivity localized to the nonepithelial cells. Taken together, our data suggest that Cox-2 is highly expressed in noninvasive bladder carcinomas, whereas the highest expression of invasive tumors associated with the invading cells, and that Cox-2 may also have a pathophysiological role in nonneoplastic conditions of the urinary bladder, such as ulcerations and inflammatory pseudotumors.

Adult↗
PubMed2001

Increased expression of cyclooxygenase-2 in malignant pheochromocytomas.

Pheochromocytomas are rare tumors of the adrenal medulla or the paraganglion system. There are no histological or chemical markers available that define the malignant behavior of these tumors; so far only the discovery of metastases reveals malignancy. Cyclooxygenase (Cox) is the key enzyme in conversion of arachidonic acid to PGs, and two isoforms, Cox-1 and Cox-2, have been identified. Cox-2 has been associated with carcinogenesis, and it is overexpressed in many human malignancies. We have now investigated the expression of Cox-2 in normal adrenal gland, in 92 primary pheochromocytomas and in six metastases using immunohistochemistry and Northern blot and Western blot analyses. Cox-2 protein was expressed in the adrenal cortex, whereas the medulla was negative as detected by immunohistochemistry. Interestingly, all malignant pheochromocytomas (n = 8), regardless of the primary location of the tumor, showed moderate or strong Cox-2 immunoreactivity, whereas 75% of the benign adrenal tumors (n = 36) showed no or only weak immunopositivity. The staining was negative or weak in 79% of the adrenal tumors that showed histologically suspicious features (n = 24), but had not metastasized. Most of the pheochromocytoma samples studied also expressed low levels of Cox-2 mRNA. Our data show that normal adrenal medulla does not express Cox-2 immunohistochemically. However, strong Cox-2 protein expression was found in malignant pheochromocytomas, whereas most benign tumors expressed Cox-2 only weakly. To our knowledge, this is the first report on Cox-2 expression in pheochromocytomas and enhanced expression in malignant pheochromocytomas. These findings suggest that negative or weak Cox-2 expression in pheochromocytomas favors benign diagnosis.

Adolescent↗
PubMed2001

Regulated expression of prostaglandin E(2) receptors EP2 and EP4 in human ovarian granulosa-luteal cells.

Prostaglandins (PGs) have been implicated in regulation of ovarian function. We have previously shown that the expression of cyclooxygenase-2 and the receptor for PGF(2 alpha) are expressed in periovulatory human granulosa cells and upregulated by gonadotropins and cytokines in cultured human ovarian granulosa-luteal (GL) cells. We now show that transcripts for PGE(2) receptor subtypes EP2 and EP4 are expressed in freshly isolated human granulosa cells and in mouse ovaries as detected by Northern blot analysis. However, EP2 and EP4 receptor mRNA levels were low or nondetectable in cultured human GL cells suggesting that these transcripts may be under hormonal and/or cytokine regulation in the ovaries in vivo. Indeed, the proinflammatory cytokine interleukin-1 beta (IL-1 beta) stimulated expression of EP2 and EP4 transcripts in concentration- and time-dependent manner in the GL cells. Furthermore, the transcript for EP2 receptor was localized in the corpus luteum of the mouse ovary by in situ hybridization, and EP2 protein was expressed in human corpus luteum as detected by immunohistochemistry. Our data suggest that IL-1 beta induces expression of EP2 and EP4 receptors in human GL cells, and that EP2 receptor is expressed in both human and murine luteal glands.

Animals↗
PubMed2001

Expression of cyclooxygenase-2 in dysplasia of the stomach and in intestinal-type gastric adenocarcinoma.

PURPOSE: Cyclooxygenase (Cox) is the key enzyme in conversion of arachidonic acid to prostanoids. Two Cox genes have been cloned, and expression of Cox-2 mRNA and protein has been shown to be elevated in several human malignancies and in animal models of carcinogenesis. The purpose of this study was to investigate Cox-2 protein expression in human gastric dysplasias and adenocarcinomas. EXPERIMENTAL DESIGN: Performance of several Cox-2 antibodies was evaluated, after which Cox-2 protein expression was studied in 67 gastric cancer specimens and in eight definitive dysplasias by using immunohistochemistry. RESULTS: Cox-2 positivity was detected in 58% (25/43) of the intestinal-type (well-differentiated) tumors and 6% (1/18) of diffuse-type (poorly differentiated) tumors. Consistent with these data, we detected higher expression of Cox-2 mRNA, protein, and enzymatic activity in well-differentiated gastric cancer cell lines (MKN-28 and MKN-74) when compared with poorly differentiated cell lines (HSC-39 and KATO III). Cox-2 immunoreactivity was localized to the carcinoma cells, but the stroma of the tumors was negative. However, strong Cox-2 positivity was consistently detected in stromal cells at sites of erosions and ulcerations. Furthermore, four of nine (44%) definitive dysplasias of the stomach that showed no evidence of invasion were positive for Cox-2. CONCLUSIONS: Cox-2 is expressed by the neoplastic cells in the intestinal-type gastric adenocarcinoma and by precarcinogenic (dysplastic) lesions leading to this disease.

Adenocarcinoma↗
PubMed2001

Molecular analysis of sulindac-resistant adenomas in familial adenomatous polyposis.

PURPOSE: Sulindac causes the reduction of adenomas in familial adenomatous polyposis (FAP) patients, but complete regression is unusual, and breakthrough of colorectal carcinoma during sulindac treatment has been described. The molecular features related to sulindac resistance are unknown. Therefore, we investigated molecular alterations in adenomas from FAP patients with complete adenoma regression on sulindac (responsive patients) and from FAP patients with sulindac-resistant adenomas (resistant patients). DESIGN: Fourteen baseline adenomas (removed before sulindac treatment) from six responsive patients were studied. Also, 9 baseline adenomas and 34 resistant adenomas (removed during sulindac treatment) from three resistant patients were analyzed. Using immunohistochemistry, we evaluated the expression of beta-catenin, cyclooxygenase-2 (Cox-2), p53, Bcl-2, and Bax. K-ras codon 12 mutations, loss of heterozygosity at 5q (APC locus), and microsatellite instability were studied with PCR-based techniques. RESULTS: There were no significant differences between baseline adenomas from sulindac-responsive and -resistant patients (P > 0.05). There was less loss of membranous beta-catenin staining and less nuclear beta-catenin accumulation in resistant adenomas compared with baseline adenomas from the same (sulindac-resistant) patients (P < 0.01) or baseline adenomas from responsive patients (P < 0.01). Epithelial Cox-2 expression was less, though not significant, in resistant adenomas compared with baseline adenomas from resistant patients, but was significantly less in baseline adenomas from responsive patients (P < 0.01). K-ras mutations were found in 8 of 34 resistant adenomas (24%) and in none of the baseline adenomas (P < 0.05). Stromal Cox-2 expression, staining of p53 and Bcl-2, and loss of heterozygosity at 5q were comparable in both groups. Loss of Bax staining and microsatellite instability were not found in any adenoma. CONCLUSIONS: Sulindac-resistant adenomas display less alteration in beta-catenin staining and less epithelial Cox-2 expression when compared with adenomas removed before sulindac treatment. K-ras mutations may contribute to sulindac-resistance. Continued research is needed to investigate molecular alterations related to sulindac resistance.

Adenoma↗
PubMed2000

The Bmx tyrosine kinase is activated by IL-3 and G-CSF in a PI-3K dependent manner.

Cytoplasmic protein tyrosine kinases play crucial roles in signaling via a variety of cell surface receptors. The Bmx tyrosine kinase, a member of the Tec family, is expressed in hematopoietic cells of the granulocytic and monocytic lineages. Here we show that Bmx is catalytically activated by interleukin-3 (IL-3) and granulocyte-colony stimulating factor (G-CSF) receptors. Activation of Bmx required phosphatidylinositol 3-kinase (PI-3K) as demonstrated by the ability of PI-3K inhibitors to block the activation signal. A green fluorescent protein (GFP) tagged Bmx was translocated to cellular membranes upon co-expression of a constitutively active form of PI-3K, further indicating a role for PI-3K in signaling upstream of Bmx. The expression of wild type Bmx in 32D myeloid progenitor cells resulted in apoptosis in the presence of G-CSF, while cells expressing a kinase dead mutant of Bmx differentiated into mature granulocytes. However, Bmx did not modulate IL-3-dependent proliferation of the cells. These results demonstrate distinct effects of Bmx in cytokine induced proliferation and differentiation of myeloid cells, and suggest that the stage specific expression of Bmx is critical for the differentiation of myeloid cells. Oncogene (2000) 19, 4151 - 4158

Animals↗