The human oncogene c-fos is homologous to the Finkel-Biskis-Jinkins (FBJ) murine osteosarcoma virus oncogene. FOS
was the first transcription factor identified that has a critical function in regulating the development of cells destined to
form and maintain the skeleton. FOS is also a major component of the activator protein-1 (AP-1) transcription factor
complex, which includes members of the JUN family.
The FOS and JUN oncoproteins form dimeric complexes that stimulate transcription of genes containing AP-1
regulatory elements.
NCBI Summary:
The Fos gene family consists of 4 members: FOS, FOSB, FOSL1, and FOSL2. These genes encode leucine zipper proteins that can dimerize with proteins of the JUN family, thereby forming the transcription factor complex AP-1. As such, the FOS proteins have been implicated as regulators of cell proliferation, differentiation, and transformation. In some cases, expression of the FOS gene has also been associated with apoptotic cell death. [provided by RefSeq, Jul 2008]
General function
Cell death/survival, Oncogenesis, Nucleic acid binding, DNA binding, Transcription factor
Comment
The AP-1 family member FOS blocks transcriptional activity of the nuclear receptor steroidogenic factor 1. Sirianni R et al. Steroid production in the adrenal zona glomerulosa is under the control of angiotensin II (Ang II), which, upon binding to its receptor, activates protein kinase C (PKC) within these cells. PKC is a potent inhibitor of the steroidogenic enzyme CYP17. We have demonstrated that, in the ovary, PKC activates expression of FOS, a member of the AP-1 family, and increased expression of this gene is linked to CYP17 downregulation. However, the pathway and the molecular mechanism responsible for the inhibitory effect of PKC on CYP17 expression are not defined. Herein, we demonstrated that Ang II inhibited CYP17 through PKC and ERK1/2-activated FOS and that blocking FOS expression decreased PKC-mediated inhibition. Although CYP17 transcription was activated by the nuclear receptor SF-1, expression of FOS resulted in a decrease in SF-1-mediated gene transcription. FOS physically interacted with the hinge region of SF-1 and modulated its transactivity, thus preventing binding of cofactors such as SRC1 and CBP, which were necessary to fully activate CYP17 transcription. Collectively, these results indicate a new regulatory mechanism for SF-1 transcriptional activity that might influence adrenal zone-specific expression of CYP17, a mechanism that can potentially be applied to other steroidogenic tissues.
The FOS/AP-1 regulates metabolic changes and cholesterol synthesis in human periovulatory granulosa cells. Choi Y et al. (2021) FOS, a subunit of the activator protein-1 (AP-1) transcription factor, has been implicated in various cellular changes. In the human ovary, the expression of FOS and its heterodimeric binding partners JUN, JUNB, and JUND increases in periovulatory follicles. However, the specific role of the FOS/AP-1 remains elusive. The present study determined the regulatory mechanisms driving the expression of FOS and its partners and functions of FOS using primary human granulosa/lutein cells (hGLC). hCG induced a biphasic increase in the expression of FOS, peaking at 1-3h and 12h. The levels of JUN proteins were also increased by hCG, with varying expression patterns. Co-immunoprecipitation analyses revealed that FOS is present as heterodimers with all JUN proteins. hCG immediately activated PKA and p42/44MAPK signaling pathways, and inhibitors for these pathways abolished hCG-induced increases in the levels of FOS, JUN, and JUNB. To identify the genes regulated by FOS, high throughput RNA sequencing was performed using hGLC treated with hCG ± T-5224 (FOS inhibitor). Sequencing data analysis revealed that FOS inhibition affects the expression of numerous genes, including a cluster of genes involved in the periovulatory process such as matrix remodeling, prostaglandin synthesis, glycolysis, and cholesterol biosynthesis. qPCR analysis verified hCG-induced, T-5224-regulated expression of a selection of genes involved in these processes. Consistently, hCG-induced increases in metabolic activities and cholesterol levels were suppressed by T-5224. This study unveiled potential downstream target genes of and a role for the FOS/AP-1 complex in metabolic changes and cholesterol biosynthesis in granulosa/lutein cells of human periovulatory follicles.////////////////// Analysis of Tyrosine Phosphorylation and AP-1 Transcription Factors c-Jun, Jun D, and Fos Family During Early Ovarian Follicle Development in the Mouse Oktay KH, et al .
The growth control mechanism of early-stage ovarian follicles is unknown. Tyrosine phosphorylation of signaling molecules and changes in expression and activation of AP-1 transcription factors have been implicated in growth regulation of numerous cell types. In this study, we used immunohistochemistry to analyze tyrosine phosphorylation patterns and expression and activation of selected AP-1 transcription factors in mouse ovarian follicles. The ovaries were collected from B62F1/J mice in estrus. Representative sections were immunostained for phosphotyrosine, phospho-c-Jun, Jun D, and c-Fos. Phosphotyrosine staining was perioocytic from the transitional stage until approximately 5 to 7 layers of granulosa cells had formed. Perioocytic staining was then replaced by scattered stippled staining in granulosa cells of larger follicles. Phospho c-Jun was exclusively expressed in mitotic granulosa cells of follicles from transitional to antral stages. Jun D was expressed in the oocytes of primordial, primary, or transitional follicles and disappeared at the 2-layer preantral stage. Fos was present in corpora lutea and theca cells but not in granulosa cells. Collectively, these data indicate that phosphotyrosine signaling and AP-1 transcription factors are intimately involved in early stages of ovarian follicle growth.
Expression regulated by
FSH, LH
Comment
FOS, a Critical Downstream Mediator of PGR and EGF-signaling Necessary for Ovulatory Prostaglandins in the Human Ovary. Choi Y et al. (2018) Fos null mice failed to ovulate and form a corpus luteum even when given exogenous gonadotropins, suggesting that ovarian Fos expression is critical for successful ovulation and CL formation. However, little is known about FOS in the human ovary. To determine the expression, regulation, and function of FOS in human periovulatory follicles. Timed periovulatory follicles were obtained from normally cycling women. Granulosa/lutein cells were collected from IVF patients. The in vivo expression after human chorionic gonadotropin (hCG) administration and in vitro regulation of FOS, JUN, JUNB, and JUND were evaluated at the mRNA and protein level. Binding of PGR and FOS to their target genes was assessed by ChIP analyses. Prostaglandin (PG)E2 and progesterone were measured. The expression of FOS, JUNB, and JUND drastically increased in ovulatory follicles after hCG administration. In human granulosa/lutein cell cultures, hCG increased the expression of FOS and JUN proteins. Inhibitors of PGR and epidermal growth factor (EGF) receptors reduced hCG-induced increases in the expression and phosphorylation of FOS. PGR bound to the FOS gene. A selective FOS inhibitor blocked hCG-induced increases in PGE2 and the expression of PG synthases and transporters (PTGES, SLCO2A1, and ABCC1). FOS bound to the promoter regions of these genes. The increase of FOS/AP-1 in human periovulatory follicles after hCG administration is mediated by collaborative actions of PGR and EGF-signaling and critical for the up-regulated expression of key ovulatory genes required for the rise in ovulatory PG in human granulosa cells.//////////////////
Ness JM, et al reported gonadotropin regulation of c-fos and c-jun messenger
ribonucleic acids in cultured rat granulosa cells.
Granulosa cells obtained from diethylstilbestrol
(DES)-treated weanling rats were challenged with follicle-stimulating hormone
(FSH), luteinizing hormone (LH), human chorionic gonadotropin (hCG), dibutyryl
cAMP ((Bu)2cAMP) or tetradecanoyl-13-phorbol acetate (TPA) either 2.5 h after
cell isolation (day 0) or following a 2-day pretreatment with FSH (day 2). Freshly
isolated cells treated with FSH exhibited 4-fold and 3-fold increases in c-fos and
c-jun mRNAs, respectively, within 30 min. Two hours after FSH treatment, both
c-fos and c-jun message levels diminished to near control levels. Granulosa cells
pretreated for 2 days with FSH, then re-challenged with FSH, showed similar
increases in both c-fos and c-jun messages. These effects were dose- and
time-dependent on both day 0 and day 2. Likewise, (Bu)2cAMP also increased
c-fos and c-jun mRNAs in a time- and dose-dependent manner on both day 0 and
day 2. In contrast, LH or hCG minimally increased c-fos and c-jun mRNAs on day
0, but on day 2, both hormones markedly increased message levels in a manner
similar to that seen with FSH. Analogous effects were observed with TPA which
minimally stimulated c-fos and c-jun mRNAs on day 0, but markedly increased
these messages on day 2. These studies demonstrate that c-fos and c-jun mRNAs
can be induced in cultured rat granulosa cells by acute gonadotropin, (Bu)2cAMP
or phorbol ester treatment and suggest that these immediate early proto-oncogenes
may play a role in granulosa cell function.
Ovarian localization
Granulosa
Comment
Delidow BC, et al 1990 reported the gonadotropin induction of c-fos and c-myc expression and
deoxyribonucleic acid synthesis in rat granulosa cells.
In this study the acute effects of PMSG on protooncogene expression,
DNA synthesis, and steroid secretion were examined. The levels of c-fos, c-myc,
and beta-actin mRNA were measured in total RNA samples from granulosa cells
by quantitative polymerase chain reaction. PMSG increased the mRNA levels of
c-fos, c-myc, and beta-actin within 15 min. Fos and myc proteins were localized
within granulosa cells by immunocytochemistry. Less than 10% of granulosa cells
stained for c-fos or c-myc proteins in the control samples. In contrast,
approximately 40% of the cells stained for these protooncogene proteins 30 min
after PMSG injection (P less than 0.05). These values declined to about 10% of
the cells 60 min after PMSG injection.
Delidow BC et al 1992 reported regulation of proto-oncogene expression and deoxyribonucleic
acid synthesis in granulosa cells of perifused immature rat
ovaries.
In the first study, granulosa cells (GCs) were harvested from
immature rat ovaries after 15, 30, or 60 min of perifusion and DNA synthesis
(3H-thymidine incorporation) and proto-oncogene mRNA levels were
determined. The presence of c-myc and c-fos proteins was localized within GCs
immunocytochemically. GCs of control ovaries exhibited modest levels of DNA
synthesis and proto-oncogene expression. FSH/insulin (IN) not only stimulated DNA
synthesis but also increased c-myc, c-fos, and c-jun mRNA levels and the
percentage of cells staining for c-fos and c-myc proteins.
Follicle stages
Antral, Preovulatory
Comment
Phenotypes
PCO (polycystic ovarian syndrome)
Mutations
2 mutations
Species: mouse
Mutation name: None
type: null mutation fertility: subfertile Comment:Johnson et al. (1992) found similar results. Homozygous mutants showed reduced placental and
fetal weights and significant loss of viability at birth. However, approximately 40% of the homozygous mutants
survived and grew at normal rates until severe osteopetrosis, characterized by foreshortening of the long bones,
ossification of the marrow space, and absence of tooth eruption, began to develop at approximately 11 days. Among
other abnormalities, these mice showed delayed or absent gametogenesis, lymphopenia, and altered behavior.
Species: human
Mutation name: None
type: naturally occurring fertility: subfertile Comment: Steroidogenic Regulatory Factor FOS Is Underexpressed in Polycystic Ovary Syndrome (PCOS) Adipose Tissue and Genetically Associated with PCOS Susceptibility. Jones MR et al. Context:Polycystic ovary syndrome (PCOS) is a heterogeneous common genetic disorder characterized by hyperandrogenemia and insulin resistance. Alterations in gene expression profiles of the ovary and adipose tissue identified the candidate gene FBJ murine osteosarcoma viral oncogene homolog (FOS) for further investigation of expression changes in metabolic tissues and genetic studies.Objective:The objective of the study was to confirm the underexpression of the FOS gene in sc adipose and determine whether variants in this gene are risk factors for PCOS.Design:RT-PCR was performed in sc fat from women with and without PCOS. Genotyping of single-nucleotide polymorphisms in the FOS locus was performed to test for association with PCOS.Setting:The study was conducted at a tertiary care academic institution.Participants:Twenty-two PCOS and 13 control subjects were recruited for gene expression studies. We assembled a discovery genotyping cohort of 354 cases and 161 controls and a replication cohort of 476 cases and 315 controls, all of whom were Caucasian.Main Measurements:Gene expression by quantitative real-time RT-PCR, FOS genotype, and PCOS status were measured.Results:FOS expression was confirmed to be reduced in PCOS adipose tissue. Three single-nucleotide polymorphisms were significantly associated with PCOS in the discovery cohort (rs8006998, P = 0.0031; rs8013918, P = 0.0006; rs8013942, P = 0.0087). rs8006998 was also associated with PCOS in the replication cohort (P = 0.013).Conclusions:Differential gene expression in sc fat and genetic association at the FOS locus in PCOS subjects implicates a role for this transcription factor in PCOS. FOS dysfunction may be a common factor between hyperandrogenism and insulin resistance.