The oncogene JUN is the putative transforming gene of avian sarcoma virus 17; it appears to be derived from a gene of
the chicken genome and has homologs in several other vertebrate species. (The name JUN comes from the Japanese
'ju-nana,' meaning the number 17.) JUN was thought to be identical to the transcription factor AP1. The FOS and JUN oncoproteins form dimeric complexes that stimulate transcription of genes containing AP-1
regulatory elements.
Cell-type-selective induction of c-jun by TAF4b directs ovarian-specific transcription networks. Geles KG et al. Cell-type-selective expression of the TFIID subunit TAFII105 (renamed TAF4b) in the ovary is essential for proper follicle development. Although a multitude of signaling pathways required for folliculogenesis have been identified, downstream transcriptional integrators of these signals remain largely unknown. Here, we show that TAF4b controls the granulosa-cell-specific expression of the proto-oncogene c-jun, and together they regulate transcription of ovary-selective promoters. Instead of using cell-type-specific activators, our findings suggest that the coactivator TAF4b regulates the expression of tissue-specific genes, at least in part, through the cell-type-specific induction of c-jun, a ubiquitous activator. Importantly, the loss of TAF4b in ovarian granulosa cells disrupts cellular morphologies and interactions during follicle growth that likely contribute to the infertility observed in TAF4b-null female mice. These data highlight a mechanism for potentiating tissue-selective functions of the basal transcription machinery and reveal intricate networks of gene expression that orchestrate ovarian-specific functions and cell morphology.
NCBI Summary:
This gene is the putative transforming gene of avian sarcoma virus 17. It encodes a protein which is highly similar to the viral protein, and which interacts directly with specific target DNA sequences to regulate gene expression. This gene is intronless and is mapped to 1p32-p31, a chromosomal region involved in both translocations and deletions in human malignancies.
Sharma SC, et al 2000 reported the regulation of AP1 (Jun/Fos) Factor expression and activation in
ovarian granulosa cells. The expression patterns of Jun
and Fos family members in response to hormones(FSH and LH) were distinct.
c-Jun, JunB, c-Fos and Fra2 were rapidly but transiently induced by FSH in
immature granulosa cells. JunD and Fra2 were induced by LH and maintained as
granulosa cells terminally differentiated into luteal cells. FSH and forskolin
induced expression of AP1 factors by A-kinase-dependent (Fra2) and
A-kinase-independent mechanisms (c-Fos, JunB), one of which involves
p38MAPK. Forskolin and PMA acted synergistically to enhance transcription of
an AP1(-73COL)-luciferase construct. JunD appears to be one mediator of this
affect, since JunD was a major component of the AP1/DNA binding complex in
granulosa cells. Thus, FSH and LH induce specific AP1 factors, their
expression patterns are distinct and that of JunD and Fra2 correlates with
differentiation of ovarian granulosa cells to luteal cells.
Jun proteins modulate the ovary-specific promoter of aromatase gene in ovarian granulosa cells via a cAMP-responsive element Ghosh S, et al .
Estrogen is critical to both normal mammary gland and breast cancer development. Circulating levels of estrogen in premenopausal women are primarily determined by the action of aromatase in ovarian granulosa cells that converts testosterone to estradiol. In the current study, we unraveled an important role of Jun proteins in modulating ovary-specific aromatase expression. Ectopic expression of the Jun proteins in a human granulosa cell line significantly inhibited an ovary-specific promoter (PII) of the aromatase gene, whereas expression of dominant-negative mutants of Jun led to increased promoter activity. The Jun-mediated repression was specific to the aromatase promoter, as Jun proteins stimulated known AP1-responsive promoters in the same cellular context. Both the activation and basic leucine zipper domains of Jun were required for the transcriptional repression. Electrophoretic gel mobility assay showed that endogenous Jun proteins bound to a functionally important cAMP-responsive element (CRE) in the PII promoter-proximal region. Alteration of the CRE-like site impaired both the cAMP-responsive transcriptional activation and Jun-mediated repression. Furthermore, chromatin immunoprecipitation indicated the presence of cJun at the proximal region of the native PII promoter. Taken together, our work suggests that Jun proteins may attenuate estrogen biosynthesis by directly downregulating transcription of the aromatase gene in ovarian granulosa cells.
Expression regulated by
FSH, LH
Comment
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.
Ovarian localization
Granulosa, Luteal cells
Comment
Rusovici R, et al 2003 reported the expression and Distribution of AP-1 Transcription Factors in the Porcine Ovary.
The activator protein-1 (AP-1) transcription factors are important regulators of cell proliferation and differentiation. The developmental distribution of AP-1 family members in porcine ovary has not been previously investigated. The authors examined the expression of AP-1 factors in porcine ovarian follicles, granulosa cells, and corpora lutea at different stages of development. Immunoblot analyses confirmed that c-Jun, JunD, JunB, c-Fos, Fra-1, Fra-2, and FosB immunoreactive proteins were present in whole-cell extracts (WCE) of all antral follicles and midluteal phase corpora lutea (CL) as well as granulosa cells (GC) isolated from different-sized antral follicles. The intensities of c-Jun and c-Fos protein bands were decreased in CL WCE compared to antral follicles. In granulosa cells from preovulatory follicles (8-10 mm), Fra-2 exhibited a shift from 43 kDa to 46 kDa when compared to granulosa cells from smaller antral follicles. Separation of cytoplasmic and nuclear extracts was performed to determine if developmental differences between these fractions existed. Most AP-1 factors predominated in the nuclear fraction with notable exceptions. c-Fos predominated in the nucleus in GC and follicles but predominated in the cytoplasmic fraction of CL. With the exception of GC from 1-2-mm follicles, in which expression was similar between fractions, Fos-B was found predominantly in the cytoplasmic fraction. Fra-1 exhibited similar expression between cytoplasmic and nuclear fractions for all tissues. Immunohistochemical (IHC) analyses of porcine ovary sections were performed to determine the cellular distribution of these factors at different follicular stages, and immunopositive nuclei were evaluated. In primordial and primary unilaminar follicles, all AP-1 factors studied except for FosB were detected in granulosa nuclei. Granulosa cell nuclei of multilaminar preantral follicles were immunopositive for all factors, with lower expression of FosB. Antral follicles exhibited GC and thecal cell nuclear staining for all factors with the exception of FosB in theca. Luteal cells exhibited the most intense nuclear staining for JunD and Fra-2, whereas all other factors were present in luteal cell nuclei although to a lesser extent. IHC with FosB antibodies yielded mostly cytoplasmic staining but only weak luteal nuclear staining. In corpora albicantia, low levels of staining were seen for all AP-1 factors. The DNA-binding abilities of these factors in granulosa cells and CL were evaluated by EMSA. Nuclear extracts from granulosa cells from 1-2-mm or 8-10-mm antral follicles bound an AP-1 DNA consensus sequence and complexes consisted predominantly of c-Jun, JunD, JunB, c-Fos, and Fra-2. In CL, c-Jun, JunD, JunB, and Fra-2 were present in DNA-binding complexes, and c-Fos binding was not detected. In conclusion, the results suggest that expression and DNA-binding activity of AP-1 factors in follicular structures changes with luteinization. Differentiation to the luteal phenotype involves a reduction in nuclear c-Jun and c-Fos and a predominance of JunD and Fra-2.
Follicle stages
Secondary, Antral, Preovulatory, Corpus luteum
Comment
Immunohistochemical 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.