• HCV core protein modulates Rb pathway through pRb down-regulation and E2F-1 up-regulation.

• Id-1 delays senescence but does not immortalize keratinocytes.

• Id proteins at the cross-road of development and cancer.

• Regulation of MyoD gene transcription and protein function by the transforming domains of the adenovirus E1A oncoprotein.

• C-myc and tumour suppressor gene product expression in developing and term human trophoblast.

1
UI - 11341983
AU - Cho J; Baek W; Yang S; Chang J; Sung YC; Suh M
TI - HCV core protein modulates Rb pathway through pRb down-regulation and E2F-1 up-regulation.
SO - Biochim Biophys Acta 2001 Feb 5;1538(1):59-66
AD - Department of Microbiology, College of Medicine, Seonam University, Namwon, South Korea.
It has been recognized that the HCV (hepatitis C virus) core protein plays an important role in hepatocarcinogenesis. The functional inactivation of the Rb pathway appears to be a major event for multi-step cancer carcinogenesis. To elucidate the role of the HCV core protein in hepatocarcinogenesis, we investigated the effect of the HCV core protein on the Rb pathway in both Rat-1 cell lines, stably expressing the HCV core protein and the doxycycline-regulated cell lines. The HCV core stable transfectants showed a dramatic decrease in the pRb levels and E2F-1 up-regulation. In the doxycycline-regulated cell lines, the pRb levels were significantly decreased which are followed by E2F-1 up-regulation. HCV core stable transfectants showed higher cell growth rates and were sensitize to apoptosis. Thus, our results first indicate that the HCV core protein decreases the expression of pRb, thereby allowing E2F-1 to be constitutively active, which is thought to result in rapid cell proliferation or sensitizing to apoptosis.

2
UI - 10908559
AU - Nickoloff BJ; Chaturvedi V; Bacon P; Qin JZ; Denning MF; Diaz MO
TI - Id-1 delays senescence but does not immortalize keratinocytes.
SO - J Biol Chem 2000 Sep 8;275(36):27501-4
AD - Department of Pathology and the Department of Medicine, Loyola University Medical Center, Maywood, Illinois 60153, USA. bnickol@lumc.edu
Defining the molecular basis responsible for regulating the proliferative potential of keratinocytes has important implications for normal homeostasis and neoplasia of the skin. Under current culture conditions, neonatal foreskin-derived human keratinocytes possess a relatively short replicative lifespan. Recently it was reported that forced overexpression of the helix-loop-helix protein Id-1 was capable of immortalizing keratinocytes, secondary to activation of telomerase activity and suppression of p16/Rb-mediated growth arrest pathways. To investigate the relationship between Id-1, telomerase activity, telomere length, p16, Rb cell cycle regulators, and senescence, whole populations of keratinocytes were infected with a retrovirus to induce overexpression of Id-1. In these unselected cultures, enhanced Id-1 levels clearly extended the lifespan of keratinocytes, but Id-1 did not prevent the onset of replicative senescence. Under these experimental conditions, Id-1 expression did not trigger induction of telomerase activity, and there was progressive shortening of the telomeres that was accompanied by elevated p16 levels and prevalence of active Rb. The ability of Id-1 to postpone, but not prevent, senescence may be related to partial inhibition of p16 expression, as the Id-1-overexpressing cultures displayed a decreased capacity for 12-O-tetradecanoylphorbol-13-acetate-mediated p16 induction. Thus, while no immortalization was observed, Id-1 could delay the onset of replicative senescence in unselected human keratinocyte populations.

3
UI - 11840325
AU - Lasorella A; Uo T; Iavarone A
TI - Id proteins at the cross-road of development and cancer.
SO - Oncogene 2001 Dec 20;20(58):8326-33
AD - Department of Neurology, Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
A large body of evidence has been accumulated that demonstrates dominant effects of Id proteins on different aspects of cellular growth. Generally, constitutive expression of Id not only blocks cell differentiation but also drives proliferation. In some settings, it is sufficient to render cells immortal or induce oncogenic transformation. The participation of Id proteins in advanced human malignancy, where they are frequently deregulated, has been dramatically bolstered by the recent discovery that Id exert pivotal contributions to many of the essential alterations that collectively dictate malignant growth. Relentless proliferation associated with self-sufficiency in growth signals and insensitivity to growth inhibitory signals, sustained neoangiogenesis, tissue invasiveness and migration capabilities of tumor cells all share dependency on the unlimited availability of Id proteins. It is remarkable that many of these features recapitulate those physiologically propelled by Id proteins to support normal development. We propose that the participation of Id in multiple fundamental traits of cancer may be the basis for unprecedented therapeutic opportunities.

4
UI - 8381218
AU - Caruso M; Martelli F; Giordano A; Felsani A
TI - Regulation of MyoD gene transcription and protein function by the transforming domains of the adenovirus E1A oncoprotein.
SO - Oncogene 1993 Feb;8(2):267-78
AD - Istituto Biologia Cellulare, CNR, Rome, Italy.
It has been demonstrated that the adenovirus E1A gene products inhibit myogenic differentiation in the mouse C2 muscle cell line. During myogenic differentiation, cell growth and tissue-specific gene expression are mutually exclusive. Since E1A exerts multiple effects on different cellular pathways through alteration of cell growth control and transcriptional regulation, we investigated in more detail the molecular mechanisms underlying the inhibitory effect of E1A on myogenic differentiation. To this end, we used mutant derivatives of E1A that lack the 'conserved domain' sequences to which the functional domains of E1A have been mapped, and we observed the effect of constitutive expression of these E1A mutants on myogenesis in the murine C2 muscle cell line. Our results demonstrate that E1A interferes with myogenesis through at least two mechanisms: (i) the inhibition of MyoD expression; (ii) the repression of MyoD-dependent transcriptional activation. In addition, we demonstrate also that the repression of MyoD transcription depends upon sequences located in the N-terminus of E1A and correlates well with the site of E1A/p300 association. Further, the inhibition of transcriptional activation by MyoD depends both on conserved region 1 and on conserved region 2, the two transforming domains of E1A. We demonstrate also that a similar inhibitory effect on the MyoD transactivating function is provided by the polyomavirus and SV40 large T oncoproteins.

5
UI - 7937596
AU - Roncalli M; Bulfamante G; Viale G; Springall DR; Alfano R; Comi A;
TI - Maggioni M; Polak JM; Coggi G C-myc and tumour suppressor gene product expression in developing and term human trophoblast.
SO - Placenta 1994 Jun;15(4):399-409
AD - II Department of Pathology, University of Milan, School of Medicine, Italy.
Proliferation and differentiation of villous trophoblast during placental development, from an early stage to full-term, were investigated in routinely fixed and processed tissues, by means of the immunocytochemical localization of the cell cycle-related proto-oncogene c-myc and the p53 and retinoblastoma susceptibility (Rb) tumour-suppressor gene products. The proliferative activity of the trophoblast was determined using an antibody against proliferating cell nuclear antigen (PCNA) which stains all proliferating cells in paraffin-embedded tissues. Diffuse nuclear immunoreactivity for PCNA, c-myc and Rb gene products was a consistent finding in early cytotrophoblast; c-myc product expression was also detectable in both layers of mid-gestation trophoblast. Only scattered cytotrophoblastic nuclei of early gestational placenta displayed immunostaining for p53 gene product. In full-term placenta c-myc expression was undetectable while Rb gene product and PCNA immunoreactivity declined markedly. These results indicate that the expression of the above genes is spatio-temporally regulated during placental development. A potential involvement of the oncosuppressor gene products p53 and Rb in the control of trophoblastic proliferation and of c-myc in the control of both the proliferative and differentiation pathways of trophoblastic cells is suggested.

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