Induction of FOS and JUN proteins by adrenocorticotropin and phorbol ester but not by 3',5'-cyclic adenosine monophosphate derivatives.

Kimura, E; Sonobe, M.; Armelin, M C S; Armelin, Hugo A.

doi:10.1210/mend.7.11.8114760

Cited by 20 publications

(16 citation statements)

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“…5) occurs subsequent to the activation of MAP kinase by ACTH (Fig. 2) and also appears to be mediated by a protein kinase C-dependent pathway rather than by a cAMP-dependent mechanism (10,11). The observations that ACTH and serum stimulate c-FOS accumulation more rapidly than does FGF (Fig.…”

Section: Discussionmentioning

confidence: 95%

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Unmasking a Growth-promoting Effect of the Adrenocorticotropic Hormone in Y1 Mouse Adrenocortical Tumor Cells

Lotfi

Todorović

Armelin

et al. 1997

Journal of Biological Chemistry

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The growth-inhibitory effects of the adrenocorticotropic hormone (ACTH) 1 on adrenal cells in vitro are well documented. ACTH-induced inhibition of cell proliferation has been observed in the Y1 mouse adrenocortical tumor cell line (1) as well as in normal adrenocortical cells isolated from a variety of species including rat, cow, and human (for review, see Ref.2). ACTH arrests dividing adrenal cells by interfering with progression through the G 1 phase of the cell cycle (3) and inhibits the initiation of DNA synthesis in G 1 -arrested cells following addition of serum or growth factors (4, 5). Several lines of evidence indicate that the growth-inhibitory effect of ACTH is mediated by cAMP with the most compelling data arising from studies of Y1 adrenal tumor cells harboring dominant inhibitory mutations in cAMP-dependent protein kinase (PKA) that specifically disrupt cAMP-dependent signaling pathways (6). These PKA mutants are resistant to the growth-inhibitory actions of ACTH and cAMP analogs (7,8), indicating that cAMP and PKA are obligatory components of this effect of ACTH on cell proliferation. The inhibition of proliferation seen in isolated adrenocortical cells contrasts sharply with the growth-promoting effects of ACTH on the adrenal gland in vivo and has led to the widely held view that ACTH serves as an indirect mitogen for the adrenal cortex in intact animals (2). Paradoxically, however, ACTH induces expression of genes often associated with enhanced cell proliferation such as ornithine decarboxylase (9) and fos and jun protooncogenes (10 -12) in isolated adrenocortical cells, raising the possibility of an underlying growth-promoting action of the hormone.The MAP kinase cascade, an important regulator of cell cycle progression, has been used recently as a biochemical marker to evaluate the status of hormones and growth factors as mitogens. Activation of the MAP kinase pathway is involved in the mitogenic effects of growth factors such as epidermal growth factor, platelet-derived growth factor, and FGF (13, 14), acting via receptor tyrosine kinases and also appears to mediate the mitogenic effects of thyrotropin on thyrocytes (15), angiotensin II on smooth muscle cells (16), and thrombin on fibroblasts (17), each acting through a G protein-coupled receptor. Conversely, inhibition of the MAP kinase cascade accompanies the growthinhibitory effects of cAMP observed in fibroblasts and other cell types (for review, see Ref. 18). In the present study, we examined the regulation of the MAP kinase pathway in Y1 mouse adrenocortical tumor cells to reconcile the growth-inhibiting effect of ACTH in vitro with the conflicting biochemical data that suggests an underlying mitogenic effect of the hormone. Although we expected that ACTH would inhibit MAP kinase activity in Y1 cells, consistent with the growth-inhibitory effects of the hormone, we find that ACTH activates the MAP kinase cascade via a signaling mechanism that is cAMP-independent. This effect of ACTH on MAP kinase prompted us to reexamine the effects of...

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Section: Discussionmentioning

confidence: 95%

“…4. At the indicated intervals, coverslips were incubated with a rabbit polyclonal antibody monospecific for mouse c-FOS (Santa Cruz Biotechnology, Inc., Santa Cruz, CA), and immune complexes were visualized by immunoperoxidase staining using a Vectastain Elite ABC kit (Vector Labs, Inc., Burlingame, CA) as described previously (11).…”

Section: Discussionmentioning

confidence: 99%

Unmasking a Growth-promoting Effect of the Adrenocorticotropic Hormone in Y1 Mouse Adrenocortical Tumor Cells

Lotfi

Todorović

Armelin

et al. 1997

Journal of Biological Chemistry

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mentioning

confidence: 96%

“…ACTH and cAMP induced immediate early gene expression with quite different kinetics (11). The immediate early gene expression profile induced by ACTH in Y1 cells resembled the expression profile induced by stimulating the PKC pathway with phorbol esters (11). In addition, c-myc mRNA levels were induced by the PKC activator 12-Otetradecanoylphorbol-13-acetate (TPA), and ACTH-induced cmyc expression was blocked by the PKC inhibitor H-7 in rat primary adrenal cell cultures (10).…”

mentioning

confidence: 99%

“…Early and delayed gene expression is elicited by ACTH (5). The immediate early genes junB, c-myc, and c-fos were stimulated by ACTH in cultured adrenocortical cells (10), and c-fos and c-jun mRNAs were induced by ACTH in the Y1 adrenal cell line (11). The steroidogenic P-450 genes, including P-450 side chain cleavage (CYP11A1), are induced in a more delayed manner in both the adrenal cortex in vivo and in Y1 cells (5).…”

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confidence: 99%

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Adrenocorticotropin Induction of Stress-activated Protein Kinase in the Adrenal Cortex in Vivo

Watanabe¹,

Peña²,

Albanese³

et al. 1997

Journal of Biological Chemistry

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Deconstructing the molecular mechanisms of cell cycle control in a mouse adrenocortical cell line: Roles of ACTH

Rocha

Forti

Lepique

et al. 2003

Microscopy Res & Technique

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This is a progress report of an attempt to deconstruct the signaling network underlying cell cycle control in the mouse Y1 adrenocortical cell line, aiming to uncover ACTH growth regulatory pathways. Y1 adrenocortical tumor cells possess amplified and overexpressed c-Ki-ras proto-oncogene. Despite this oncogenic lesion, Y1 cells retain tight regulatory mechanisms of cell cycle control typified by the sequential events comprising the mitogenic response triggered by FGF2 in G0/G1-arrested Y1 cells: 1) activation of ERK1/2 and PI3K, by 5 minutes; 2) induction of c-Fos and c-Myc proteins by 2 hours; 3) induction of cyclin D1 protein by 5 hours; 4) phosphorylation of Rb protein between 6 and 8 hours; 5) onset of DNA synthesis by 8-9 hours. In this cell line, ACTH-receptor (ACTH-R) activates contradictory pathways of growth regulation. First, ACTH coordinately induces fos and jun gene families via activation of both ERK1/2 and cAMP/PKA pathways, resembling a mitogen. Second, ACTH-R triggers cAMP/PKA-mediated antimitogenic mechanisms comprised of Akt/PKB dephosphorylation/deactivation, c-Myc protein degradation, and p27(Kip1) protein induction. Induction of cyclin D1 depends on activation of both ERK1/2 and PI3K, but is not affected by ACTH action. As a consequence, ACTH antagonizes FGF2 mitogenic activity but ectopic expression of the c-Myc protein (via MycER fusion protein) is sufficient to abrogate this ACTH antagonistic effect over FGF2 mitogenic activity. Ectopic expression of both c-Myc and cyclin D1 is not sufficient to drive G0/G1-arrested Y1 cells into S phase, but when the sustained expression of these two proteins is complemented by ACTH treatment it promotes G1 phase progression and DNA synthesis initiation. In conclusion, ACTH-receptor lacks signaling potential sufficient to initiate a mitogenic response in Y1 adrenocortical cells and, therefore, cannot substitute for bona fide mitogens like FGF2.

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Induction of FOS and JUN proteins by adrenocorticotropin and phorbol ester but not by 3',5'-cyclic adenosine monophosphate derivatives.

Cited by 20 publications

References 20 publications

Unmasking a Growth-promoting Effect of the Adrenocorticotropic Hormone in Y1 Mouse Adrenocortical Tumor Cells

Unmasking a Growth-promoting Effect of the Adrenocorticotropic Hormone in Y1 Mouse Adrenocortical Tumor Cells

Adrenocorticotropin Induction of Stress-activated Protein Kinase in the Adrenal Cortex in Vivo

Deconstructing the molecular mechanisms of cell cycle control in a mouse adrenocortical cell line: Roles of ACTH

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