Origin and phylogenetic relationships of [4Fe-4S]-containing O2 sensors of bacteria.

The advent of environmental O2 about 2.5 billion years ago forced microbes to metabolically adapt and to develop mechanisms for O2 sensing. Sensing of O2 by [4Fe-4S]2+ to [2Fe-2S]2+ cluster conversion represents an ancient mechanism that is used by FNREc (Escherichia coli), FNRBs (Bacillus subtilis), NreBSa (Staphylococcus aureus) and WhiB3Mt (Mycobacterium tuberculosis). The phylogenetic relationship of these sensors was investigated. FNREc homologues are restricted to the proteobacteria and a few representatives from other phyla. Homologues of FNRBs and NreBSa are located within the bacilli, of WhiB3 within the actinobacteria. Archaea contain no homologues. The data reveal no similarity between the FNREc , FNRBs , NreBSa and WhiB3 sensor families on the sequence and structural levels. These O2 sensor families arose independently in phyla that were already present at the time O2 appeared, their members were subsequently distributed by lateral gene transfer. The chemistry of [4Fe-4S] and [2Fe-2S] cluster formation and interconversion appears to be shared by the sensor protein families. The type of signal output is, however, family specific. The homologues of FNREc and NreBSa vary with regard to the number of Cys residues that coordinate the cluster. It is suggested that the variants derive from lateral gene transfer and gained other functions.

Perceptions of patient expectation for an antibiotic: a comparison of walk-in centre nurses and GPs.

BACKGROUND: Patient expectation for a prescription is a recognized influence on GPs' prescribing, particularly in relation to the prescribing of antibiotics. Nurses are now able to supply antibiotics under a Patient Group Direction (PGD) in NHS walk-in centres and may experience similar pressures in this new role. OBJECTIVES: Our aim was to compare walk-in centre nurses' and GPs' perceptions of the influence of patient expectation on their supply of an antibiotic to patients with an acute respiratory tract infection presenting with a sore throat or cough. METHODS: Between June and December 2001, all patients presenting with a sore throat or cough at six walk-in centres and six nearby general practices were eligible to participate in the study. After the health professional-patient consultation, the health professional and the patient each completed a questionnaire. RESULTS: There were 472 health professional (181 GPs and 291 walk-in centres) and 160 (34%, 160 out of 472) patient questionnaires returned. GPs were more likely to report that the patient expected an antibiotic than nurses (72% of 181 versus 13% of 291, P < 0.001). GPs were also less likely to report that an antibiotic was indicated than nurses (88% of 136 versus 97% of 194, P < 0.001). There was a trend for doctors to prescribe more frequently than nurses, in 74% of 180 patients versus 66% of 291 patients (P = 0.06). GPs were likely to report that the patient expected an antibiotic when the patient reported wanting a prescription (60% of 68, P = 0.05) and to report that the patient expected an antibiotic if the patient thought an antibiotic would be beneficial (62% of 68, P = 0.001). There was a much weaker relationship between nurse perceptions of patient expectation for an antibiotic and, either patient desire for a prescription or the patient's affirmative belief that an antibiotic would be beneficial. CONCLUSIONS: Nurses may be compensating for a lack of security in their new role as antibiotic suppliers by not acknowledging the influence of patient expectation on their decision making. The acknowledgement of the influence of patient expectation might be beneficial to nurses' development as suppliers of medicines by giving them greater understanding of the consultation process and in the need to discuss patient expectations explicitly in the consultation.

Expression of HNF4alpha isoforms in mouse liver development is regulated by sequential promoter usage and constitutive 3' end splicing.

Hepatocyte nuclear factor 4alpha (HNF4alpha) is essential for the establishment and maintenance of liver-specific gene expression. The HNF4alpha gene codes for several isoforms whose developmental and physiological relevance has not yet been explored. HNF4alpha1 and HNF4alpha7 originate from different promoters, while alternative splicing in 3' leads to HNF4alpha2 and HNF4alpha8, respectively. HNF4alpha7/alpha8 were abundantly expressed in embryonic liver and fetal-like hepatoma cells. HNF4alpha1/alpha2 transcripts were up-regulated at birth and represented the only isoforms in adult-like hepatoma cells. In line with its expression profile, HNF4alpha7 activated more avidly than HNF4alpha1 reporter plasmids for genes that are expressed early. The expression patterns of both isoforms together with the differences observed in their transcriptional activities provide elements accounting for fine-tuning of the activity of HNF4alpha. The sequential expression of HNF4alpha7/alpha8 and HNF4alpha1/alpha2 during mouse liver development is the only modification in liver-enriched transcription factors thus far recorded, which parallels the transition from the fetal to the adult hepatic phenotype.

GPs' attitudes to minor ailments.

BACKGROUND: It is generally considered that a significant proportion of 'inappropriate' demand for GP services is generated by consultations for minor ailments. How GPs manage minor ailments is likely to affect how patients perceive and handle similar illnesses in the future. Whilst this potentially has significant implications for general practice workload, research investigating GP' attitudes towards minor ailments and their management is sparse. OBJECTIVE: Our aim was to describe GP' experiences and perceptions of minor ailment consultations and their attitudes towards minor ailment management. METHODS: A questionnaire survey was conducted in 1999, derived from a series of 20 qualitative interviews with practising GPs. The survey was sent to one GP randomly selected from each practice (n = 759) in eight English health authorities. Attitudinal statements were analysed using factor analysis. RESULTS: Four hundred and fourteen GPs (54.5%) completed and returned the questionnaire. Respondents were consulted regularly about minor illness or symptoms, with almost all (95.6%) having experienced a minor ailment consultation in the previous week. Factor analysis suggested four issues to be of importance in determining GP' attitudes to minor ailment management. These were attitudes towards pharmacists, attitudes towards patient empowerment, frustration with minor ailment consultations and attitudes towards caution/risk. CONCLUSION: Although GPs are clearly frustrated by the level of minor ailment consultations, this study suggests that there may be complex factors which influence their attitudes. For the optimal management of minor ailments, inter-professional relationships potentially are of great importance. With increasing patient demand, it is essential that finite health care resources are accessible, appropriate and used in an optimal way.

Conserved as well as divergent regulatory elements account for expression of the human and rodent phenylalanine hydroxylase genes.

We have uncovered a fundamental difference in the regulation of the rodent and the human phenylalanine hydroxylase (PAH) genes: expression of human PAH is independent of glucocorticoids and/or cAMP in contrast to the mouse gene which is not only highly inducible but dependent upon hormones for expression. Nevertheless, the two genes do exhibit similarities: DNaseI hypersensitive sites are identically located in the regulatory regions, and the sequences around these sites are partially conserved and associated with regulatory elements sharing similar function. In transient transfections, the human proximal promoter is tissue-specific and presents significant activity compared to the extremely low and ubiquitous activity of the mouse promoter. DNA fragments corresponding to the two upstream hypersensitive sites of both genes have enhancer activity that depends upon the liver-enriched transcription factor binding sites for hepatocyte nuclear factor (HNF) 1 and/or CCAAT/enhancer binding protein (C/EBP). While expression of the rodent gene relies upon two modules in the HSIII enhancer, one activated by HNF1 and C/EBP and the other required for the hormone response, the human equivalent has conserved only the liver-specific transcription factor binding module. Even though the more proximal enhancer is not necessary for full reporter gene activity in transient transfection assays in Pah-expressing hepatoma cells, this enhancer could be required in both species for activation during development.

Hormone response of rodent phenylalanine hydroxylase requires HNF1 and the glucocorticoid receptor.

Expression of the rodent phenylalanine hydroxylase (PAH) gene is dependent upon hormones. Induction by glucocorticoids and cAMP occurs slowly and maximal stimulation is obtained by a synergistic effect of the two compounds. Hormone responsiveness is conferred by the tissue-specific HSIII enhancer and involves (i) protein kinase A mediating the cAMP response, even though a consensus sequence for binding of the cAMP response element binding protein is not present; (ii) other serine/threonine kinases as deduced from inhibitor studies; (iii) glucocorticoid receptor protein bound to glucocorticoid response element half sites; and (iv) binding of the liver-enriched transcription factor hepatocyte nuclear factor 1 (HNF1) to sites in the enhancer. Glucocorticoid receptor and HNF1, bound to their cognate sites, cooperatively increase the glucocorticoid response of the PAH gene, this response being synergistically enhanced by cAMP after long-term treatment.

An enhancer element 6 kb upstream of the mouse HNF4alpha1 promoter is activated by glucocorticoids and liver-enriched transcription factors.

We have characterized a 700 bp enhancer element around -6 kb relative to the HNF4alpha1 transcription start. This element increases activity and confers glucocorticoid induction to a heterologous as well as the homologous promoters in differentiated hepatoma cells and is transactivated by HNF4alpha1, HNF4alpha7, HNF1alpha and HNF1beta in dedifferentiated hepatoma cells. A 240 bp sub-region conserves basal and hormone-induced enhancer activity. It contains HNF1, HNF4, HNF3 and C/EBP binding sites as shown by DNase I footprinting and electrophoretic mobility shift assays using nuclear extracts and/or recombinant HNF1alpha and HNF4alpha1. Mutation analyses showed that the HNF1 site is essential for HNF1alpha transactivation and is required for full basal enhancer activity, as is the C/EBP site. Glucocorticoid response element consensus sites which overlap the C/EBP, HNF4 and HNF3 sites are crucial for optimal hormonal induction. We present a model that accounts for weak expression of HNF4alpha1 in the embryonic liver and strong expression in the newborn/adult liver via the binding sites identified in the enhancer.

GP survey response rate: a miscellany of influencing factors.

BACKGROUND: GP response to surveys is acknowledged to vary widely. The minimization of non-response bias and the generalizability of findings are fundamental research issues. OBJECTIVE: The aim of this study was to identify the factors that had influenced GPs' decisions to complete a questionnaire. METHODS: A short questionnaire eliciting GPs' views on minor ailment consultations was sent to 759 GPs from eight English health authorities. The response rate was 54.5%. Factors perceived by respondents to have influenced their decision to complete this questionnaire were also assessed. Subsequently, a feedback summary, together with a short evaluation form, was sent to those GPs requesting it. RESULTS: The response from GPs located in the London area was significantly lower than that from those elsewhere. Respondents identified questionnaire length and the originating institution as the two major factors influencing their decision to return the survey. A single mailing of the evaluation form yielded a response rate of >60% predominantly positive comments. CONCLUSION: Many factors influence a GP's decision to complete a survey. The effect of location has, to date, largely been ignored. Furthermore, this study suggested feedback to be an important issue. Within health services research, all possible factors need to be considered to maximize response, reduce non-response bias and ultimately facilitate the dissemination of findings.

Muscle-regulated expression and determinants for neuromuscular junctional localization of the mouse RIalpha regulatory subunit of cAMP-dependent protein kinase.

In skeletal muscle, transcription of the gene encoding the mouse type Ialpha (RIalpha) subunit of the cAMP-dependent protein kinase is initiated from the alternative noncoding first exons 1a and 1b. Here, we report that activity of the promoter upstream of exon 1a (Pa) depends on two adjacent E boxes (E1 and E2) in NIH 3T3-transfected fibroblasts as well as in intact muscle. Both basal activity and MyoD transactivation of the Pa promoter require binding of the upstream stimulating factors (USF) to E1. E2 binds either an unknown protein in a USF/E1 complex-dependent manner or MyoD. Both E2-bound proteins seem to function as repressors, but with different strengths, of the USF transactivation potential. Previous work has shown localization of the RIalpha protein at the neuromuscular junction. Using DNA injection into muscle of plasmids encoding segments of RIalpha or RIIalpha fused to green fluorescent protein, we demonstrate that anchoring at the neuromuscular junction is specific to RIalpha subunits and requires the amino-terminal residues 1-81. Mutagenesis of Phe-54 to Ala in the full-length RIalpha-green fluorescent protein template abolishes localization, indicating that dimerization of RIalpha is essential for anchoring. Moreover, two other hydrophobic residues, Val-22 and Ile-27, are crucial for localization of RIalpha at the neuromuscular junction. These amino acids are involved in the interaction of the Caenorhabditis elegans type Ialpha homologue R(CE) with AKAP(CE) and for in vitro binding of RIalpha to dual A-kinase anchoring protein 1. We also show enrichment of dual A-kinase anchoring protein 1 at the neuromuscular junction, suggesting that it could be responsible for RIalpha tethering at this site.

Type I protein kinase a is localized to interphase microtubules and strongly associated with the mitotic spindle.

We show here that type I protein kinase A is localized to microtubules during the entire cell cycle in epithelial (hepatoma, cervical carcinoma) and nonepithelial (myoblast) cell lines. The association of the type Ialpha regulatory subunit is very strong in all phases of mitosis, from prophase to cytokinesis. In interphase, the association appears weaker, reflecting perhaps a more dynamic molecular interaction. This regulatory subunit appears to recruit catalytic subunits as the latter are also associated with microtubules. BW1J hepatoma cells, stably transfected with either wild-type or mutant Ialpha regulatory subunit, are enriched in aberrant mitoses with multipolar spindles and in mono- or multinucleated giant cells. This suggests that type I protein kinase A could have a role in centrosome duplication and/or segregation, sister chromatid separation, or cytokinesis.

Inhibition of MMH (Met murine hepatocyte) cell differentiation by TGF(beta) is abrogated by pre-treatment with the heritable differentiation effector FGF1.

MMH (Met murine hepatocyte) liver cells derived from transgenic mice expressing a truncated constitutively active form of human c-Met are non-transformed immortalized cell lines. We have previously shown that they harbor: (1) epithelial cells that express the liver-enriched transcription factors HNF4 and HNF1(alpha), and that can be stably induced by FGF1 to express liver functions, and (2) fibroblast-like bi-potential palmate cells that can differentiate into bile duct-like structures in Matrigel cultures, or into epithelial cells competent to express hepatic functions. Low concentrations of TGF(beta) have been found to inhibit growth and differentiation of MMH cells. The factor stabilized the palmate cell phenotype, and it provoked epithelial cells to acquire palmate-like morphological characteristics, in parallel with down-regulation of expression of HNF4 and HNF1(alpha) and activation of Snail transcripts. The effects of TGF(beta) were dominant if it was added with FGF1, but the effects on differentiation were abrogated if cells had been pre-treated with FGF1. This work identifies TGF(beta) as a factor that could be implicated in maintaining bi-potential precursor cells in the liver, FGF1 as one that could over-ride the TGF(beta) effects and Snail as a candidate for mediation of the signal.

British community pharmacists' views of physician-assisted suicide (PAS).

OBJECTIVES: To explore British community pharmacists' views on PAS, including professional responsibility, personal beliefs, changes in law and ethical guidance. DESIGN: Postal questionnaire. SETTING: Great Britain. SUBJECTS: A random sample of 320 registered full-time community pharmacists. RESULTS: The survey yielded a response rate of 56%. The results showed that 70% of pharmacists agreed that it was a patient's right to choose to die, with 57% and 45% agreeing that it was the patient's right to involve his/her doctor in the process and to use prescription medicines, respectively. Forty-nine per cent said that they would knowingly dispense a prescription for use in PAS were it to be legalized and 54% believed it correct to refuse to dispense such a prescription. Although 53% believed it to be their right to know when they were being involved in PAS, 28% did not. Most pharmacists (90%) said that they would wish to see the inclusion of a practice protocol for PAS in the code of ethics of the Royal Pharmaceutical Society of Great Britain (CE-RPSGB) in the event of a change in the law on PAS. In addition, 89% would wish to see PAS included in the Conscience Clause of the CE-RPSGB. Males were found to be significantly less likely to favour PAS than females (p < 0.05), as were those declaring an ethnic/religious background of consideration when dealing with ethical issues in practice compared with their counterparts (p < 0.00005). CONCLUSION: Pharmacists view their professional responsibility in PAS to be more obligatory than a physician's, in having to provide the means for PAS. It is worrying that a proportion of the respondents prefer to remain in ignorance of the true purpose of a prescription for PAS; a finding at odds with current developments within the pharmaceutical profession. A practice protocol for PAS and an extension of the conscience clause should be considered in the event of PAS becoming legal. Such measures would allow the efficient provision of the pharmaceutical service whilst at the same respecting the personal beliefs of those who object to cooperating in the ending of a life.

Alternative 5'-exons of the mouse cAMP-dependent protein kinase subunit RIalpha gene are conserved and expressed in both a ubiquitous and tissue-restricted fashion.

The activity of cAMP-dependent protein kinase is controlled by its regulatory subunits. Mouse RIalpha regulatory subunit expression is initiated from five different non-coding 5'-regions (exons 1a, 1b, 1c, 1d and 1e). This organization appears to be conserved among species. All mouse tissues accumulate exon 1a and 1b transcripts and most contain more 1b than 1a, except brain, heart and oesophagus. Exon 1d and 1e transcripts are found in several tissues, while exon 1c is testis-specific. All five transcripts are in RIalpha-rich tissues: gonads and adrenal glands.

Identification of a bipotential precursor cell in hepatic cell lines derived from transgenic mice expressing cyto-Met in the liver.

Met murine hepatocyte (MMH) lines were established from livers of transgenic mice expressing constitutively active human Met. These lines harbor two cell types: epithelial cells resembling the parental populations and flattened cells with multiple projections and a dispersed growth habit that are designated palmate. Epithelial cells express the liver-enriched transcription factors HNF4 and HNF1alpha, and proteins associated with epithelial cell differentiation. Treatments that modulate their differentiation state, including acidic FGF, induce hepatic functions. Palmate cells show none of these properties. However, they can differentiate along the hepatic cell lineage, giving rise to: (a) epithelial cells that express hepatic transcription factors and are competent to express hepatic functions; (b) bile duct-like structures in three-dimensional Matrigel cultures. Derivation of epithelial from palmate cells is confirmed by characterization of the progeny of individually fished cells. Furthermore, karyotype analysis confirms the direction of the phenotypic transition: palmate cells are diploid and the epithelial cells are hypotetraploid. The clonal isolation of the palmate cell, an immortalized nontransformed bipotential cell that does not yet express the liver-enriched transcription factors and is a precursor of the epithelial-hepatocyte in MMH lines, provides a new tool for the study of mechanisms controlling liver development.

Phenotypic effects of the forced expression of HNF4 and HNF1alpha are conditioned by properties of the recipient cell.

Tagged versions of HNF4 or HNF1alpha cDNAs in expression vectors have been introduced by transient and stable transfection into three cell lines of hepatic origin that all fail to express these two liver-enriched transcription factors and hepatic functions. C2 and H5 cells are dedifferentiated rat hepatoma variants and WIF12-E cells are human fibroblast-rat hepatoma hybrids with a reduced complement of human chromosomes. Transfectants were analyzed for the expression state of the endogenous genes coding for these transcription factors and for hepatic functions. Each cell line showed a different response to the forced expression of the transcription factors. In C2 cells, no measurable effect was observed, either upon transitory or stable expression. H5 cells reexpressed the endogenous HNF4 gene only upon transient HNF1alpha transfection, and the endogenous HNF1alpha gene only in stable HNF4 transfectants. WIF12-E cells responded to the forced transient or stable expression of either HNF1alpha or HNF4 by cross-activation of the corresponding endogenous gene. In addition, the stable transfectants reexpress HNF3alpha and C/EBPalpha, as well as all of the hepatic functions examined. Hybrid cells similar to WIF12-E had previously been observed to show pleiotropic reexpression of the hepatic phenotype in parallel with loss of human chromosome 2. For the stable WIF12-E transfectants, it was verified that reexpression of the hepatic phenotype was not due to loss of human chromosome 2. The demonstration of reciprocal cross-regulation between HNF4 and HNF1alpha in transient as well as stable transfectants implies that direct effects are involved.

Differences in fatigue by treatment methods in women with breast cancer.

PURPOSE/OBJECTIVES: To investigate the differences between various cancer therapies (radiation, hormonal, chemotherapy, and their combinations) and the specific dimensions of fatigue (affective meaning, behavioral/severity, cognitive/mood, and sensory). DESIGN: Descriptive, cross-sectional, mailed survey design. SAMPLE AND SETTING: Data were collected from women who were breast cancer survivors and members of a nonprofit educational organization in the North-east. Criteria for this study included no self-reported disease recurrence, and treatment was within 18 months prior to the mailed survey (N = 322). The typical participant was middle-aged (mean = 52.2; SD = 10.3), Caucasian (93%), postmenopausal (55%), and diagnosed with cancer 2.42 (SD = 2.6) years prior to the study. METHODS: Secondary data analysis from a study using the Piper Fatigue Scale. VARIABLES: Level of fatigue. FINDINGS: Significant differences were found by treatment in total fatigue scores (p < 0.03) and cognitive/mood scores (p < 0.05). Women who received combination therapy had the highest fatigue scores (mean = 4.8; SD = 2.0); those who received only radiation therapy had the lowest fatigue scores (mean = 2.7; SD = 2.0). CONCLUSIONS: Fatigue in breast cancer survivors varies by type of cancer therapy. Future studies are needed to investigate the relationships between fatigue and hormonal therapy, and they need to be designed to examine changes over time. IMPLICATIONS FOR NURSING PRACTICE: Study findings advance knowledge about fatigue in women with breast cancer and aid nurses in providing anticipatory guidance for women undergoing different treatment regimens.

The revised Piper Fatigue Scale: psychometric evaluation in women with breast cancer.

PURPOSE/OBJECTIVES: To confirm the multidimensionality of the Piper Fatigue Scale (PFS) and to reduce the total number of PFS items without compromising reliability and validity estimates. DESIGN: Methodologic, part of a larger, cross-sectional, mailed survey design study. SETTING: Urban and suburban area in the northeast United States. SAMPLE: As part of the larger study, 2,250 surveys were distributed to women survivors of breast cancer who were on a mailing list for the educational organization Living Beyond Breast Cancer, 715 surveys (32%) were returned. Of these, 382 women met this methodologic study's criteria for having completed each of the 40 items on the PFS. The average respondent was 50 years old, postmenopausal, and treated with combination cancer therapy. METHODS: Principal axes factor analysis with oblique rotation. MAIN RESEARCH VARIABLES: Fatigue factors/subscales. FINDINGS: Five factors/subscales were identified initially. Because the fifth factor contained only two items (ability to bathe/wash and ability to dress), these items and the associated factor/subscale were dropped from the final solution. An additional nine items, not loading on any factor (> 0.40), also were dropped. The remaining items and factors/subscales were reviewed to ensure that the criteria were met: a pattern of inter-item correlations between 0.30-0.70; a minimum number of five or more items/subscale; standardized alpha for the subscales and total scale of at least 0.89; and absence of gender-specific items. CONCLUSIONS: The revised version of the PFS consists of 22 items and four subscales: behavioral/severity (6 items), affective meaning (5 items), sensory (5 items) and cognitive/mood (6 items). Standardized alpha for the entire scale (n = 22 items) is 0.97, indicating that some redundancy still may exist among the items. Additional revisions await further testing. IMPLICATIONS FOR NURSING PRACTICE: As fatigue is acknowledged to be the most frequent symptom experienced by patients with cancer, accurate measurement and assessment is essential to advance not only the science of fatigue but, most importantly, to evaluate the efficacy of intervention strategies on patient and family outcomes.

Hepatocyte nuclear factor 4 provokes expression of epithelial marker genes, acting as a morphogen in dedifferentiated hepatoma cells.

We have recently shown that stable expression of an epitope-tagged cDNA of the hepatocyte- enriched transcription factor, hepatocyte nuclear factor (HNF)4, in dedifferentiated rat hepatoma H5 cells is sufficient to provoke reexpression of a set of hepatocyte marker genes. Here, we demonstrate that the effects of HNF4 expression extend to the reestablishment of differentiated epithelial cell morphology and simple epithelial polarity. The acquisition of epithelial morphology occurs in two steps. First, expression of HNF4 results in reexpression of cytokeratin proteins and partial reestablishment of E-cadherin production. Only the transfectants are competent to respond to the synthetic glucocorticoid dexamethasone, which induces the second step of morphogenesis, including formation of the junctional complex and expression of a polarized cell phenotype. Cell fusion experiments revealed that the transfectant cells, which show only partial restoration of E-cadherin expression, produce an extinguisher that is capable of acting in trans to downregulate the E-cadherin gene of well-differentiated hepatoma cells. Bypass of this repression by stable expression of E-cadherin in H5 cells is sufficient to establish some epithelial cell characteristics, implying that the morphogenic potential of HNF4 in hepatic cells acts via activation of the E-cadherin gene. Thus, HNF4 seems to integrate the genetic programs of liver-specific gene expression and epithelial morphogenesis.

Liver-enriched transcription factors uncoupled from expression of hepatic functions in hepatoma cell lines.

Among the liver-enriched transcription factors identified to date, only expression of hepatocyte nuclear factor 4 (HNF4) and hepatocyte nuclear factor 1 (HNF1) is in strict correlation with hepatic differentiation in cultured rat hepatoma cells. Indeed, differentiated hepatoma cells that stably express an extensive set of adult hepatic functions express liver-enriched transcription factors, while dedifferentiated cells that have lost expression of all these hepatic functions no longer express HNF4 and HNF1. We describe a new heritable phenotype, designated as uncoupled, in which there is a spontaneous dissociation between the expression of these transcription factors and that of the hepatic functions. Cells presenting this phenotype, isolated from differentiated hepatoma cells, cease to accumulate all transcripts coding for hepatic functions but nevertheless maintain expression of HNF4 and HNF1. Transitory transfection experiments indicate that these two factors present in these cells have transcriptional activity similar to that of differentiated hepatoma cells. Characterization of the appropriate intertypic cell hybrids demonstrates that this new phenotype is recessive to the dedifferentiated state and fails to be complemented by differentiated cells. These results indicate the existence of mechanisms that inhibit transcription of genes coding for hepatocyte functions in spite of the presence of functional HNF4 and HNF1. Cells of the uncoupled phenotype present certain properties of oval cells described for pathological states of the liver.