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Transcription factor E2F4 (E2F-4)


Inhibition of pituitary tumors in Rb mutant chimeras through E2f4 loss reveals a key suppressive role for the pRB/E2F pathway in urothelium and ganglionic carcinogenesis.

The retinoblastoma protein pRB suppresses tumorigenesis largely through regulation of the E2F transcription factors. E2F4, the most abundant E2F protein, is thought to act in cooperation with pRB to restrain cell proliferation. In this study, we analyse how loss of E2f4 affects the tumorigenicity of pRB-deficient tissues. As Rb(-/-);E2f4(-/-) germline mice die in utero, we generated Rb(-/-);E2f4(-/-) chimeric animals to allow examination of adult tumor phenotypes. We found that loss of E2f4 had a differential effect on known Rb-associated neuroendocrine tumors. It did not affect thyroid and adrenal glands tumors but partially suppressed lung neuroendocrine hyperplasia. The most striking effect was in the pituitary where E2F4 loss delayed the development, and reduced the incidence, of Rb mutant tumors. This tumor suppression increased the longevity of the Rb(-/-);E2f4(-/-) chimeric animals allowing us to identify novel tumor types. We observed ganglionic neuroendocrine neoplasms, lesions not associated earlier with mutation of either Rb or E2f4. Moreover, a subset of the Rb(-/-);E2f4(-/-) chimeras developed either low- or high-grade carcinomas in the urothelium transitional epithelium supporting a key role for Rb in bladder cancer.

MeSH Terms

  • Animals
  • Cell Transformation, Neoplastic
  • E2F4 Transcription Factor
  • Longevity
  • Mice
  • Mice, Knockout
  • Pituitary Neoplasms
  • Retinoblastoma Protein
  • Urinary Bladder
  • Urinary Bladder Neoplasms
  • Urothelium

Ghrelin receptor (GHS-R1A) agonists show potential as interventive agents during aging.

Administration of an orally active agonist (MK-0677) of the growth hormone secretagogue receptor (GHS-R1a) to elderly subjects restored the amplitude of endogenous episodic growth hormone (GH) release to that of young adults. Functional benefits include increased lean mass and bone density and modest improvements in strength. In old mice, a similar agonist partially restored function to the thymus and reduced tumor cell growth and metastasis. Treatment of old mice with the endogenous GHS-R1a agonist ghrelin restored a young liver phenotype. The mechanism involves inhibition of cyclin D3:cdk4/cdk6 activity and increased protein phosphatase-2A (PP2A) activity in liver nuclei, which stabilizes the dephosphorylated form of the transcription factor C/EBPalpha preventing the age-dependent formation of the C/EBPalpha-Rb-E2F4-Brm nuclear complex. By inhibiting formation of this complex, repression of E2F target genes is de-repressed and C/EBPalpha regulated expression of Pepck, a regulator of gluconeogenesis, is normalized, thereby restoring a young liver phenotype. In the brain, aging is associated with decline in dopamine function. We investigated the potential neuromodulatory role of GHS-R1a on dopamine action. Neurons were identified in the hippocampus, cortex, substantia nigra, and ventral tegmental areas that coexpressed GHS-R1a and dopamine receptor subtype-1 (D1R). Cell culture studies showed that, in the presence of ghrelin and dopamine, GHS-R and D1R form heterodimers, which modified G-protein signal transduction resulting in amplification of dopamine signaling. We speculate that aging is associated with deficient endogenous ghrelin signaling that can be rescued by intervention with GHS-R1a agonists to improve quality of life and maintain independence.

MeSH Terms

  • Adult
  • Aged
  • Aging
  • Animals
  • Bone Density
  • Brain
  • CCAAT-Enhancer-Binding Protein-alpha
  • Cell Nucleus
  • Cyclin D3
  • Cyclin-Dependent Kinase 4
  • Cyclin-Dependent Kinase 6
  • Cyclins
  • Dopamine
  • E2F4 Transcription Factor
  • GTP-Binding Proteins
  • Ghrelin
  • Gluconeogenesis
  • Glutathione Peroxidase
  • Human Growth Hormone
  • Humans
  • Indoles
  • Liver
  • Mice
  • Middle Aged
  • Multiprotein Complexes
  • Neoplasm Metastasis
  • Neoplasms
  • Neurons
  • Phenotype
  • Protein Phosphatase 2
  • Receptors, Dopamine
  • Receptors, Ghrelin
  • Retinoblastoma Protein
  • Signal Transduction
  • Spiro Compounds
  • Thymus Gland
  • Transcription Factors

Aging reduces proliferative capacities of liver by switching pathways of C/EBPalpha growth arrest.

The liver is capable of completely regenerating itself in response to injury and after partial hepatectomy. In liver of old animals, the proliferative response is dramatically reduced, the mechanism for which is unknown. The liver specific protein, C/EBPalpha, normally arrests proliferation of hepatocytes through inhibiting cyclin dependent kinases (cdks). We present evidence that aging switches the liver-specific pathway of C/EBPalpha growth arrest to repression of E2F transcription. We identified an age-specific C/EBPalpha-Rb-E2F4 complex that binds to E2F-dependent promoters and represses these genes. The C/EBPalpha-Rb-E2F4 complex occupies the c-myc promoter and blocks induction of c-myc in livers of old animals after partial hepatectomy. Our results show that the age-dependent switch from cdk inhibition to repression of E2F transcription causes a loss of proliferative response in the liver because of an inability to induce E2F target genes after partial hepatectomy providing a possible mechanism for the age-dependent loss of liver regenerative capacity.

MeSH Terms

  • Aging
  • Animals
  • CCAAT-Enhancer-Binding Protein-alpha
  • Cell Division
  • Cyclin-Dependent Kinases
  • DNA-Binding Proteins
  • E2F4 Transcription Factor
  • Gene Expression Regulation, Developmental
  • Genes, Regulator
  • Genes, myc
  • Hepatocytes
  • Liver
  • Liver Regeneration
  • Macromolecular Substances
  • Molecular Weight
  • Promoter Regions, Genetic
  • Rats
  • Rats, Inbred F344
  • Repressor Proteins
  • Retinoblastoma Protein
  • Signal Transduction
  • Transcription Factors

Expression patterns of retinoblastoma and E2F family proteins during corneal development.

To determine the expression patterns of the retinoblastoma protein and the E2F transcription factor families in limbal and corneal epithelia and in corneal keratocytes in situ during corneal development and differentiation. Retinoblastoma protein (pRb) and its family members p107 and p130; E2F-1, -2, and -4, members of the E2F family of transcription factors; and Ki67, a marker of actively cycling cells, were localized by indirect immunofluorescence microscopy, in corneas of neonatal, juvenile, and adult rats. Presence of mRNA for pRb, p107, p130, and E2F types 1 to 5 in adult corneal epithelium was determined by reverse transcription-polymerase chain reaction. mRNA for all members of pRb and E2F families was present in adult corneal epithelium. The greatest number of Ki67-positive corneal and limbal epithelial cells were present at days 13 to 19, and Ki67-positive stromal keratocytes at day 2. pRb and E2F-2 were localized to all cells in neonatal, juvenile, and adult corneas. With age, p130 localization became more intense and nuclear in stromal keratocytes and suprabasal cells of corneal and limbal epithelia; p107, initially nuclear in limbal and corneal epithelia, became increasingly cytoplasmic in corneal epithelium. E2F-1 was initially nuclear in keratocytes and diminished after day 10. E2F-1 was localized in the basal cell layer of limbal and corneal epithelia after day 10. E2F4 was always nuclear in limbal epithelium and cytoplasmic in corneal epithelium. Expression patterns of pRb and E2F family proteins vary with corneal cell differentiation, but are most apparent with p130 and p107. Nuclear localization of p130 appears to correlate with terminal differentiation in epithelium and entrance into a quiescent state by keratocytes. In contrast, p107 is nuclear in the undifferentiated limbal basal cells and is cytoplasmic in the remainder of the corneal epithelial cells.

MeSH Terms

  • Aging
  • Animals
  • Animals, Newborn
  • Carrier Proteins
  • Cell Cycle
  • Cell Cycle Proteins
  • Cell Differentiation
  • Cornea
  • DNA Primers
  • DNA-Binding Proteins
  • E2F Transcription Factors
  • E2F1 Transcription Factor
  • Fluorescent Antibody Technique, Indirect
  • Gene Expression
  • Ki-67 Antigen
  • RNA
  • RNA, Messenger
  • Rats
  • Rats, Sprague-Dawley
  • Retinoblastoma Protein
  • Retinoblastoma-Binding Protein 1
  • Reverse Transcriptase Polymerase Chain Reaction
  • Transcription Factor DP1
  • Transcription Factors