ICER reverses tumorigenesis of rat prostate tumor cells without affecting cell growth

Mémin, Elisabeth; Yehia, Ghassan; Razavi, Reza; Molina, Carlos A.

doi:10.1002/pros.10149

Cited by 11 publications

(12 citation statements)

References 14 publications

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“…Therefore, although deregulated proliferation by HBx was suggested to lead to cellular transformation of NHBx1, HBx-induced oncogenic transformation seemed not to be directly related to growth stimulation. Similar effects have been observed for the inducible cAMP early repressor (ICER) protein which reversed tumorigenesis of rat prostate tumor cells without affecting cell growth [31]. Moreover, overexpression of the core protein of hepatitis C virus in NIH3T3 cells resulted in rapid proliferation, although the core protein expression itself did not induce cellular transformation [32].…”

Section: Discussionsupporting

confidence: 56%

An intracellular antibody can suppress tumorigenicity in Hepatitis B virus X-expressing cells

Jin

Kwon

Kim

et al. 2005

Cancer Immunol Immunother

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Although the hepatitis B virus X protein (HBx) is thought to play a causative role in the development of hepatocellular carcinoma, it is not yet known whether interfering with HBx function may affect the cellular transformation of HBx-expressing tumor cells. To address this question, we adopted an intracellular antibody fragment expression approach to block the function of HBx. Expression of a single-chain variable fragment (scFv) specific to HBx (designated as H7scFv) inhibited HBx-dependent cellular transactivation. Furthermore, H7scFv suppressed the growth of HBx-expressing tumor cells in both soft agar and nude mice. The suppressive effect of H7scFv on tumorigenicity appeared not to be mediated by inhibition of HBx-induced growth stimulation since the growth rate of these cells was not affected significantly by H7scFv expression. In conclusion, these data suggest that the HBx-dependent transformed phenotype is reversible and that HBx may be a good molecular target for the treatment of HBV-related tumors.

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Section: Discussionsupporting

confidence: 56%

An intracellular antibody can suppress tumorigenicity in Hepatitis B virus X-expressing cells

Jin

Kwon

Kim

et al. 2005

Cancer Immunol Immunother

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“…These findings suggest a role for ICER in the modulation of leukemic gene expression. 8,9 The induction of Cyclin-A1 in patients suggests additional …”

Section: 6mentioning

confidence: 99%

cAMP response element binding protein (CREB) overexpression CREB has been described as critical for leukemia progression

Pigazzi¹,

Ricotti²,

Germanò³

et al. 2007

Haematologica

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Letters to the Editor haematologica/the hematology journal | 2007; 92(10) | 1435 | cAMP response element binding protein (CREB) overexpression CREB has been described as critical for leukemia progression CREB has been described as critical for leukemia progress. We investigated CREB expression in ALL and AML pediatric patients. CREB protein was significantly high (p<0.001) at diagnosis but not during remission. This study underlines the role of CREB in leukemia and suggests new insights into the transformation process. Haematologica 2007; 92:1435 92: -1437 Acute leukemia accounts for about one third of childhood cancers.1 Recent advances in functional genomics has highlighted the need to investigate complex gene expression patterns to discover novel signaling and disease-related pathways.2 CREB is a transcription factor that regulates gene expression principally through activation of the cyclic AMP (cAMP)-dependent cell signal transduction pathways by binding to the cAMP response element (CRE) region at the promoters.3 CREB is phosphorylated in Serine 133 principally by protein kinase A, and this modification enhances its transactivation potential.4 It has been reported to be over expressed in adult myeloid leukemia and to play a role in myeloid transformation and leukemia progression. 5,6We investigated the expression of CREB in childhood acute leukemia. We analyzed a total of 86 acute lymphoid (ALL), 40 acute myeloid (AML) leukemia patients (Table 1) and a series of leukemia cell lines to reveal the potential role of this signaling pathway in leukemogenesis. CREB expression was also studied in samples collected from 86 ALL and 21 AML patients during remission to establish a correlation with the disease stage. As control group we used bone marrow (BM) samples from 19 patients affected by other nonneoplastic hematologic disorders (diagnoses: neutropenia, n=4; thrombocytopenia, n=9; anemia, n=3; lymphoma, without BM infiltration n=3) and from 9 healthy donors (7 pediatric and 2 adult samples collected in the process of transplants).Western blot (WB) analysis showed CREB protein overexpression in all leukemia cell lines but not in sorted normal hematopoietic stem cells ( Figure 1A). WB analysis showed CREB overexpressed in 29 out of the 31 (94%) patients with ALL (20/23 with B-lineage ALL; and 7/8 with T-ALL) and in 13 out of 17 (76%) with AML. In addition, CREB resulted in the active form (pCREB) at diagnosis. On the contrary, CREB was not detected in any remission samples or in the control group. Interestingly, CREB expression in samples collected from diagnosis to treatment completion showed a clear correlation with the disease stage ( Figure 1B). To define CREB protein level, a competitive ELISA assay was performed on 16 ALL and 7 AML patients previously analyzed by WB as well as in 55 new ALL and 23 AML patients collected during the study. Average CREB concentration was 151.5 ng/mL in ALL at diagnosis (n=71), and 72 ng/mL in AML at diagnosis (n=30). The distribution of CREB level was significantly lower in A...

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“…[7][8][9] Recently, it has been proposed as a tumor suppressor gene in prostate and pituitary cancers. 10,11 We previously documented that ICER was downregulated at diagnosis of acute leukemia in a cohort of pediatric patients, whereas CREB protein was found to be overexpressed. On the contrary, the higher ICER expression was found in healthy bone marrow (BM) and during remission phases of leukemia therapy, whereas CREB expression was found to be significantly decreased.…”

Section: Introductionmentioning

confidence: 98%

ICER expression inhibits leukemia phenotype and controls tumor progression

et al. 2008

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The inducible cyclic AMP (cAMP) early repressor (ICER) and cAMP response element-binding protein (CREB) are transcriptional regulators of the cAMP-mediated signaling pathway. CREB has been demonstrated to be upregulated in the majority of childhood leukemias contributing to disease progression, whereas ICER, its endogenous repressor, was found to be downregulated. Our research focus has been the function of restored ICER expression. ICER exogenously expressed in cell lines decreases CREB protein level and induces a lowered clonogenic potential in vitro. It decreases the ability of HL60 to invade the extramedullary sites and to promote bone marrow angiogenesis in nonobese diabetic-severe combined immunodeficient mice, demonstrating its potential effects on tumor progression. ICER represses the majority of 96 target genes upregulated by CREB. It binds CRE promoters and controls gene expression restoring the normal regulation of major cellular pathways. ICER is subjected to degradation through a constitutively active form of the extracellular signal-regulated protein kinase, which drives it to the proteasome. We propose that ICER is downregulated in HL60 to preserve CREB overexpression, which disrupts normal myelopoiesis and promotes blast proliferation. These findings define the function of ICER as a tumor suppressor in leukemia. Unbalanced CREB/ICER expression needs to be considered a pathogenetic feature in leukemogenesis. The molecular characterization of this pathway could be useful for novel therapeutic strategies.

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ICER reverses tumorigenesis of rat prostate tumor cells without affecting cell growth

Cited by 11 publications

References 14 publications

An intracellular antibody can suppress tumorigenicity in Hepatitis B virus X-expressing cells

An intracellular antibody can suppress tumorigenicity in Hepatitis B virus X-expressing cells

cAMP response element binding protein (CREB) overexpression CREB has been described as critical for leukemia progression

ICER expression inhibits leukemia phenotype and controls tumor progression

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