The nuclear phosphoprotein c-Jun, encoded by the proto-oncogene c-jun, is a major component of the AP-1 complex. A potent transcriptional regulator, c-jun is also able to transform normal rat embryo cells in cooperation with an activated c-Ha-ras gene. By deletion analysis, we identified the regions of c-Jun encoding transformation and transactivation functions. Our studies indicate that there is a direct correlation between the ability of the c-Jun protein to activate transcription and cotransform rat embryo cells. The regions involved in these functions include the conserved leucine zipper/DNA binding domain and an effector domain near its N terminus. This N-terminal region spans amino acids 61 to 146 of the c-Jun protein and is highly conserved among all Jun family members. These results support the hypothesis that c-Jun transforms cells by stimulating the expression of transformation-mediating genes.
Whether or not serum selenium and vitamin E (alpha-tocopherol) concentrations were changed was examined among healthy families of lung cancer patients. Family members as a whole (115 sons and daughters of 55 patients with primary lung cancer) were found to have a trend to lower serum selenium levels (0.116 +/- SD 0.024 microgram/ml, 0.05 less than P less than 0.1). Particularly among families of adenocarcinoma patients, the mean level was significantly lower (0.111 +/- 0.019 microgram/ml, P less than 0.05) than that (0.122 +/- 0.014 microgram/ml) in age-ratio matched controls who did not have cancer patients among their second-degree relatives. Serum vitamin E levels (11.85 +/- 2.85 micrograms/ml) were significantly lower among family members of adenocarcinoma patients than the controls (14.1 +/- 3.1 micrograms/ml, P less than 0.01). Serum selenium and vitamin E levels were significantly lower in lung cancer patients (n = 37, mean age, 63.9 +/- 11.2 yr) than in the controls (P less than 0.001). These data suggest that there are familial factors in serum selenium and vitamin E levels among families of lung cancer patients.
The inducibility of sister chromatid exchanges (SCEs) by benzo(a)pyrene (BP) was studied in cultured peripheral blood lymphocytes of 15 untreated lung cancer patients and 25 healthy persons including 11 high- and 14 low-cancer-risk individuals tentatively classified by the familial history of lung cancer and other neoplasms. The baseline SCE frequency in cultured lymphocytes was significantly high in lung cancer patients, as compared with all healthy persons or low-cancer-risk individuals. Following exposure to BP, the lymphocytes of lung-cancer patients and high-cancer-risk individuals exhibited significantly greater SCE yields than those of persons at low risk, although no significant difference was observed in the lymphocyte SCE yields when the levels of lung cancer patients were compared with those of all healthy persons. A comparison of the net SCE increase (delta SCE) in BP-exposed lymphocytes among the study groups, however, revealed a significant difference in delta SCE values only between high- and low-cancer-risk individuals. The present findings on both the observed SCE yields and delta SCE values suggest that lymphocytes of high-risk individuals may be more susceptible to BP-induced DNA damage than those of persons at low risk, and that such a chromosomal hypersensitivity to genotoxins may be associated with a high risk of neoplasms.
The nuclear phosphoprotein c-Jun, encoded by the proto-oncogene c-jun, is a major component of the AP-1 complex. A potent transcriptional regulator, c-jun is also able to transform normal rat embryo cells in cooperation with an activated c-Ha-ras gene. By deletion analysis, we identified the regions of c-Jun encoding transformation and transactivation functions. Our studies indicate that there is a direct correlation between the ability of the c-Jun protein to activate transcription and cotransform rat embryo cells. The regions involved in these functions include the conserved leucine zipper/DNA binding domain and an effector domain near its N terminus. This N-terminal region spans amino acids 61 to 146 of the c-Jun protein and is highly conserved among all Jun family members. These results support the hypothesis that c-Jun transforms cells by stimulating the expression of transformation-mediating genes.
The ras oncogene product ras p21 is structurally homologous to guanine nucleotide-binding proteins and plays an important role in transducing signals elicited by membrane receptors into intracellular metabolism. We examined psoriatic tissues for expression of ras p21 and compared them with normal skin, using the indirect immunofluorescence technique with the anti-ras p21 monoclonal antibody (MoAb), rp-35. In normal epidermis of five healthy individuals and uninvolved epidermis of three psoriatic patients, only the basal layer was positively stained by rp-35. The spinous layer was negative or faintly positive. In contrast, all psoriatic epidermis obtained from 13 psoriatic patients had strong reactivity with rp-35 throughout the epidermis. There were no differences in the staining pattern of hair follicles, sebaceous glands, eccrine glands, and eccrine ducts, which positively reacted with rp-35, between psoriatic and normal skin. The functions of ras p21 have not been clearly identified in mammalian cells; however recent reports reveal that cyclic AMP production is inhibited by the transfection of activated ras gene into normal cells. Enhanced expression of ras p21 in psoriatic epidermis may be indicative of some mechanism of defective beta-adrenergic responsiveness, which is considered to be one of the important pathophysiological phenomena causing the hyperproliferative condition in psoriasis.
It is of great interest in tumor immunology to know whether oncogene products could be used not only as tumor markers for cancer diagnosis, but also as immunogens for cancer therapy. BALB/c mice immunized with syngeneic fibroblasts, Escherichia coli cells producing p60v-src, or the purified p60v-src protein extracted from the E. coli producer cells showed transplantation resistance to a Rous sarcoma virus-induced tumor but not a Kirsten sarcoma virus-induced tumor. In contrast, mice immunized with cells not producing p60v-src or their derived proteins or with chicken ovalbumin did not show any significant resistance. These findings suggest that p60v-src can act as a specific transplantation rejection antigen in mice.
The relationship of tumor size, status of disease in the TNM classification, and stage of disease to ras oncogene expression was studied in human non-small cell lung cancer materials immunohistochemically using monoclonal antibody rp-35 against ras p21. Materials of adenocarcinoma and squamous cell carcinoma obtained from primary sites larger than 30 mm in diameter exhibited intensely positive reactions with rp-35 significantly more frequently than those with primary sites, 30 mm in diameter or smaller (p < 0.01). Furthermore in the TNM classification, cases with T2 (with primary sites larger than 30 mm in diameter) or T3 (with direct extension to adjacent structures) showed significantly higher reaction with rp-35 than those with Tl (with primary sites 30 mm in diameter or smaller) (p < 0.01), although N and M status did not correlate with ras p21 expression. These results suggest that ras oncogene may play a significant role in growth or tumorigenesis at the primary site in human non-small cell lung cancer.
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