cfos and cjun antisense oligonucleotides block mitogenesis triggered by fibroblast growth factor-2 and ACTH in mouse Y1 adrenocortical cells

Lotfi, Claudimara Ferini Pacicco; Armelin, Hugo A.

doi:10.1677/joe.0.1680381

Cited by 29 publications

(33 citation statements)

References 29 publications

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“…ACTH, to some extent, resembles FGF2 by inducing transcription of c-fos, fosB and junB genes (Kimura et al 1993, Lotfi et al 1997, Lotfi & Armelin 2001, Rocha et al 2003. But, in spite of this resemblance to FGF2, ACTH is a strong antagonist of FGF2 mitogenic activity, inhibiting the cell cycle of Y1 cells by blocking G 1 progression (Armelin et al 1977, Weidman & Gill 1977, Kimura & Armelin 1988, data provided in this paper).…”

Section: Introductionmentioning

confidence: 71%

“…Although the malignant phenotype of Y1 cells includes evasion from apoptosis and a limitless replicative potential, this cell line retains control mechanisms of the G 0 <G 1 <S transition of the cell cycle, being highly responsive to mitogenic stimulation by FGF2 (Armelin et al 1996, Lotfi et al 1997, Lotfi & Armelin 2001.…”

Section: Introductionmentioning

confidence: 99%

“…In G 0 /G 1 cell cycle-arrested Y1 adrenocortical cells, FGF2 treatment elicits a strong mitogenic response that includes: (a) rapid and transient activation of ERK-MAPK (extra cellular signalregulated kinases-mitogen activated protein kinases) (2 to 10 min); (b) transcriptional activation of c-fos, c-jun and c-myc genes (10 to 30 min); (c) induction of cFos and cMyc proteins by 1 h and cyclin D1 protein by 5-6 h; and (d) onset of DNA synthesis initiation by 8-9 h (Armelin et al 1996, Lotfi et al 1997, Lotfi & Armelin 2001, Rocha et al 2003, Schwindt et al 2003. ACTH, to some extent, resembles FGF2 by inducing transcription of c-fos, fosB and junB genes (Kimura et al 1993, Lotfi et al 1997, Lotfi & Armelin 2001, Rocha et al 2003.…”

Section: Introductionmentioning

confidence: 99%

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c-Myc protein is stabilized by fibroblast growth factor 2 and destabilized by ACTH to control cell cycle in mouse Y1 adrenocortical cells

Lepique¹,

Moraes²,

Rocha³

et al. 2004

Journal of Molecular Endocrinology

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ACTH is the hormone known to control adrenal cortex function and maintenance in the intact animal but, in culture, it inhibits proliferation of adrenocortical cells from different mammalian species, a puzzle that has remained unsolved for nearly 30 years. In this paper we compare ACTH and fibroblast growth factor 2 (FGF2) antagonistic effects on the cell cycle in the Y1 cell line, a functional lineage of mouse adrenocortical tumor cells. This cell line displays chronic high levels of c-Ki-Ras-GTP, high active constitutive levels of phosphatidylinositol 3-OH kinase/Protein Kinase B (PI3K/AKT) and low constitutive basal expression of c-Myc, which accounts for a minor deregulation of the cell cycle. In G 0 /G 1 -arrested Y1 cells, over-expression of the dominant negative mutant HaRasN17 drastically reduces c-Ki-Ras-GTP levels, eliminating basal c-Myc expression and basal S phase entry. PI3K/Akt seems to be the downstream pathway from c-Ki-ras for deregulation of c-Myc basal expression, since wortmannin abolishes c-Myc expression in serum-starved, G 0 /G 1 -arrested Y1 cells. FGF2 is a strong mitogen for Y1 cells, promoting -in a manner dependent on the MEK/ERK pathway -c-myc transcription induction, c-Myc protein stabilization and S phase entry in G 0 /G 1 -arrested Y1 cells. On the other hand, ACTH causes c-Myc protein destabilization, partially blocking S phase entry induced by FGF2, by a process dependent on the cAMP/protein kinase A (PKA) pathway. The whole pathway activated by ACTH to destabilize c-Myc protein in Y1 cells might comprise the following steps: ACTH receptor , cAMP/PKA , Akt deactivation , GSK3 activity liberation , c-Myc Thr58 phosphorylation.We demonstrate that c-Myc regulation is a central key in the cell cycle control by these factors, since enforced expression of c-Myc through the MycER chimera abrogates the ACTH inhibitory effect over FGF2-induced S phase entry.

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Section: Introductionmentioning

confidence: 71%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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c-Myc protein is stabilized by fibroblast growth factor 2 and destabilized by ACTH to control cell cycle in mouse Y1 adrenocortical cells

Lepique¹,

Moraes²,

Rocha³

et al. 2004

Journal of Molecular Endocrinology

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“…E/CDK2 ! pRB pathway, leading to the induction of fos and jun expression (25) and promoting progression through G 1 , irrespective of the levels of K-Ras-GTP (Supplementary Data, Figs. S1A, S1B, and S5).…”

Section: Discussionmentioning

confidence: 99%

Fibroblast Growth Factor 2 Restrains Ras-Driven Proliferation of Malignant Cells by Triggering RhoA-Mediated Senescence

et al. 2008

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Fibroblast growth factor 2 (FGF2) is considered to be a bona fide oncogenic factor, although results from our group and others call this into question. Here, we report that exogenous recombinant FGF2 irreversibly inhibits proliferation by inducing senescence in Ras-dependent malignant mouse cells, but not in immortalized nontumorigenic cell lines. We report the following findings in K-Ras-dependent malignant Y1 adrenocortical cells and H-Ras V12-transformed BALB-3T3 fibroblasts: (a) FGF2 inhibits clonal growth and tumor onset in nude and immunocompetent BALB/c mice, (b) FGF2 irreversibly blocks the cell cycle, and (c) FGF2 induces the senescence-associated B-galactosidase with no accompanying signs of apoptosis or necrosis. The tyrosine kinase inhibitor PD173074 completely protected malignant cells from FGF2. In Y1 adrenal cells, reducing the constitutively high levels of K-Ras-GTP using the dominant-negative RasN17 mutant made cells resistant to FGF2 cytotoxicity. In addition, transfection of the dominant-negative RhoA-N19 into either Y1 or 3T3-B61 malignant cell lines yielded stable clonal transfectants that were unable to activate RhoA and were resistant to the FGF2 stress response. We conclude that in Rasdependent malignant cells, FGF2 interacts with its cognate receptors to trigger a senescence-like process involving RhoA-GTP. Surprisingly, attempts to select FGF2-resistant cells from the Y1 and 3T3-B61 cell lines yielded only rare clones that (a) had lost the overexpressed ras oncogene, (b) were dependent on FGF2 for proliferation, and (c) were poorly tumorigenic. Thus, FGF2 exerted a strong negative selection that Rasdependent malignant cells could rarely overcome. [Cancer Res 2008;68(15):6215-23]

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“…4A). Second, the G 1 phase is relatively short (Lotfi & Armelin 2001) and, moreover, cyclin D1 and E are concomitantly induced instead of being induced sequentially (Rocha & Armelin, unpublished data). This last oncogenic lesion leaves cyclin D1-CDK4/6 without any role in the regulation of G 1 phase progression (Fig.…”

Section: Discussionmentioning

confidence: 99%

Vasopressin triggers senescence in K-ras transformed cells via RhoA-dependent downregulation of cyclin D1

Forti¹,

Armelin²

2007

Endocrine Related Cancer

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Arginine vasopressin (AVP), a vasoactive peptide hormone that binds to three G-protein coupled receptors (V 1 R, V 2 R, and V 3 R), has long been known to activate V 1 R and elicit mitogenesis in several cell types, including adrenal glomerulosa cells. However, in the mouse Y1 adrenocortical malignant cell line, AVP triggers not only a canonical mitogenic response but also novel RhoA-GTP-dependent mechanisms which downregulate cyclin D1, irreversibly inhibiting K-ras oncogene-driven proliferation. In Y1 cells, AVP blocks cyclin D1 expression, induces senescence-associated b-galactosidase (SAb-Gal) and inhibits proliferation. However, ectopic expression of cyclin D1 renders Y1 cells resistant to both SAb-Gal induction and proliferation inhibition by AVP. In addition, ectopic expression of the dominant negative RhoAN19 mutant blocks RhoA activation, yielding Y1 cell sub-lines which are no longer susceptible to cyclin D1 downregulation, SAb-Gal induction, or proliferation inhibition by AVP. Furthermore, inhibiting RhoA with C3 exoenzyme protects Y1 cells from AVP proliferation inhibition and SAb-Gal induction. On the other hand, AVP treatment does not activate caspases 3 and 7, and the caspase inhibitor Ac-DEVD-CMK does not protect Y1 cells from proliferation inhibition by AVP, implying that AVP does not trigger apoptosis. These results underline a pivotal survival activity of cyclin D1 that protects K-ras oncogene-dependent malignant cells from senescence.

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cfos and cjun antisense oligonucleotides block mitogenesis triggered by fibroblast growth factor-2 and ACTH in mouse Y1 adrenocortical cells

Cited by 29 publications

References 29 publications

c-Myc protein is stabilized by fibroblast growth factor 2 and destabilized by ACTH to control cell cycle in mouse Y1 adrenocortical cells

c-Myc protein is stabilized by fibroblast growth factor 2 and destabilized by ACTH to control cell cycle in mouse Y1 adrenocortical cells

Fibroblast Growth Factor 2 Restrains Ras-Driven Proliferation of Malignant Cells by Triggering RhoA-Mediated Senescence

Vasopressin triggers senescence in K-ras transformed cells via RhoA-dependent downregulation of cyclin D1

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