Nuclear Factor 1-C2 Is Regulated by Prolactin and Shows a Distinct Expression Pattern in the Mouse Mammary Epithelial Cells during Development

Johansson, Eva; Kannius-Janson, Marie; Gritli-Linde, Amel; Bjursell, Gunnar; Nilsson, Jeanette

doi:10.1210/me.2004-0359

Cited by 20 publications

(25 citation statements)

References 33 publications

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“…Previously we have reported that prolactin is involved in maintaining the basal levels of NF1-C2 proteins in the nuclei of mammary epithelial cells in pregnant mice as well as in cells derived from a virgin mouse (15). To investigate the hypothesis that prolactin prevents NF1-C2 degradation, we incubated the double-thymidine-blocked cells with prolactin for 4 h. Western blot analysis of extracts from these cells revealed that prolactin indeed prevents degradation of NF1-C2 (Fig.…”

Section: Resultsmentioning

confidence: 93%

“…Further, using studies with mouse mammary epithelial NMuMG cells and mammary tissue from heterozygous prolactin receptor knockout mice as a basis, we have demonstrated that the prolactin signaling pathway has a role in the maintenance of the NF1-C2 protein in mammary epithelial nuclei. Since treatment with prolactin resulted in a net increase of NF1-C2 protein in the whole cell and not simply in a nuclear translocation of already present cytoplasmic proteins, we suggested that prolactin regulates NF1-C2 by a mechanism distinct from its regulation of Stat5 (15).…”

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confidence: 81%

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Nuclear Jak2 and Transcription Factor NF1-C2: a Novel Mechanism of Prolactin Signaling in Mammary Epithelial Cells

Nilsson¹,

Bjursell²,

Kannius-Janson³

2006

Molecular and Cellular Biology

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The classical mechanism by which prolactin transduces its signal in mammary epithelial cells is by activation of cytosolic signal transducer and activator of transcription 5 (Stat5) via a plasma membrane-associated prolactin receptor-Janus kinase 2 (Jak2) complex. Here we describe an alternative pathway through which prolactin via Jak2 localized in the nucleus activates the transcription factor nuclear factor 1-C2 (NF1-C2). Previous reports have demonstrated a nuclear localization of Jak2, but the physiologic importance of nuclear Jak2 has not been clear. We demonstrate that nuclear Jak2 regulates the amount of active NF1-C2 through tyrosine phosphorylation and proteasomal degradation. Our data also demonstrate a link between prolactin and p53 as well as the milk gene carboxyl ester lipase through nuclear Jak2 and NF1-C2. Hence, we describe a novel pathway through which nuclear Jak2 is subject to regulation by prolactin in mammary epithelial cells.The mammary gland is a complex organ that undergoes development and differentiation under the control of a number of hormones and growth factors, their receptors, and transcription factors. The polypeptide hormone prolactin has an essential role both in the differentiation of the gland during pregnancy and in the regulation of milk protein gene expression (13). Prolactin receptor signaling can be mediated through several different signaling pathways (2, 4, 9, 10), the principal of which in mammary epithelial cells is that through the receptor-associated tyrosine kinase Janus kinase 2 (Jak2) (21). Binding of prolactin to its receptor activates Jak2, which phosphorylates the transcription factor signal transducer and activator of transcription 5 (Stat5). Phosphorylated Stat5 dimerizes, translocates to the nucleus, and binds to its response elements (35). Both Jak2 and Stat5 have been demonstrated to be essential for mammary gland development and milk protein gene expression (23,29). Apart from the Jak2-Stat5 pathway, the target genes and factors that mediate the action of prolactin in the mammary gland under normal conditions are poorly understood.One important mechanism regulating signal transduction is that through proteolysis (6, 11). The proteasome pathway in particular plays an important role in the degradation of a number of cellular proteins (26,31). Earlier studies have shown that proteasome inhibitors prolong the activity of the Jak-Stat signaling pathway by protecting tyrosine-phosphorylated Jak2 proteins from degradation (33, 38).We have previously identified the transcription factor nuclear factor 1-C2 (NF1-C2) as an important activator of milk genes as well as the p53 tumor suppressor gene in the mouse mammary gland during pregnancy (14,16). This activity indicates that NF1-C2 might participate both in the establishment of a functional gland and in the protection of the gland against tumorigenesis during proliferation. Further, using studies with mouse mammary epithelial NMuMG cells and mammary tissue from heterozygous prolactin receptor knockout mice as a b...

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Section: Resultsmentioning

confidence: 93%

mentioning

confidence: 81%

Nuclear Jak2 and Transcription Factor NF1-C2: a Novel Mechanism of Prolactin Signaling in Mammary Epithelial Cells

Nilsson¹,

Bjursell²,

Kannius-Janson³

2006

Molecular and Cellular Biology

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“…Tissue microarrays were incubated with the affinity purified rabbit polyclonal pNF1-C2 antiserum (1:1,000 dilution) according to the protocol described in ref. 9.…”

Section: Methodsmentioning

confidence: 99%

“…Studies using mammary epithelial cells and tissue from heterozygous prolactin receptor knockout mice showed that prolactin is required for maintenance of the transcription factor nuclear factor 1-C2 (NF1-C2) in the mammary epithelium (9). The NF1 family consists of four genes (NF1-A, NF1-B, NF1-C, and NF1-X), each producing different splice variants, thereby generating a large number of protein isoforms.…”

Section: Introductionmentioning

confidence: 99%

“…The expression levels of the different NF1 genes and the ratio between alternatively spliced transcripts vary between cell types and differentiation states (10)(11)(12)(13). In the mouse mammary gland, the specific isoform NF1-C2 is the dominating NF1-C protein and exhibits a characteristic temporal pattern during the adult developmental cycle; the mRNA is constitutively present, but the protein decreases during lactation to reemerge again at involution (9). We previously described a novel pathway through which prolactin maintains NF1-C2 via activated nuclear Janus-activated kinase 2 ( Jak2; ref.…”

Section: Introductionmentioning

confidence: 99%

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Nuclear Janus-Activated Kinase 2/Nuclear Factor 1-C2 Suppresses Tumorigenesis and Epithelial-to-Mesenchymal Transition by Repressing Forkhead Box F1

et al. 2010

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Progression to metastasis is the proximal cause of most cancer-related mortality. Yet much remains to be understood about what determines the spread of tumor cells. This paper describes a novel pathway in breast cancer that regulates epithelial-to-mesenchymal transition (EMT), motility, and invasiveness. We identify two transcription factors, nuclear factor 1-C2 (NF1-C2) and Forkhead box F1 (FoxF1), downstream of prolactin/ nuclear Janus-activated kinase 2, with opposite effects on these processes. We show that NF1-C2 is lost during mammary tumor progression and is almost invariably absent from lymph node metastases. NF1-C2 levels in primary tumors correlate with better patient survival. Manipulation of NF1-C2 levels by expression of a stabilized version or using small interfering RNA showed that NF1-C2 counteracts EMT, motility, invasiveness, and tumor growth. FoxF1 was found to be a direct repressed target of NF1-C2. We provide the first evidence for a role of FoxF1 in cancer and in the regulation of EMT in cells of epithelial origin. Overexpression of FoxF1 was associated with a mesenchymal phenotype, increased invasiveness in vitro, and enhanced growth of breast carcinoma xenografts in nude mice. The relevance of these findings is strengthened by the correlation between FoxF1 expression and a mesenchymal phenoype in breast cancer cell isolates, consistent with the interpretation that FoxF1 promotes invasion and metastasis. Cancer Res; 70(5); 2020-9. ©2010 AACR.

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Nuclear JAK2: Form and Function in Cancer

Qian

Yao

2011

The Anatomical Record

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The conventional view of Janus kinase 2 (JAK2) is a nonreceptor tyrosine kinase which transmits information to the nucleus via the signal transducer and activator of transcriptions (STATs) without leaving the cytoplasm. However, accumulating data suggest that JAK2 may signal by exporting from cytoplasm to nucleus, where it guides the transcriptional machinery independent of STATs protein. Recent studies demonstrated that JAK2 is a crucial component of signaling pathways operating in the nucleus. Especially the latest landmark discovery confirmed that JAK2 goes into the nucleus and directly interacts with nucleoproteins, such as histone H3 at tyrosine 41 (H3Y41), nuclear factor 1-C2 (NF1-C2) and SWI/SNF-related helicases/ATPases (RUSH)-1a, indicating that JAK2 has a fresh nuclear function. Nuclear JAK2 is linked to a variety of cellular functions, such as cell cycle progression, apoptosis and genetic instability. The balance between these functions is an essential factor in determining whether a cell remains benign or becomes malignant. The aim of this review is intended to summarize the state of our knowledge on nuclear localization of JAK2 and nuclear JAK2 pathways, and to highlight the emerging roles for nuclear JAK2 in carcinogenesis.

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Nuclear Factor 1-C2 Is Regulated by Prolactin and Shows a Distinct Expression Pattern in the Mouse Mammary Epithelial Cells during Development

Cited by 20 publications

References 33 publications

Nuclear Jak2 and Transcription Factor NF1-C2: a Novel Mechanism of Prolactin Signaling in Mammary Epithelial Cells

Nuclear Jak2 and Transcription Factor NF1-C2: a Novel Mechanism of Prolactin Signaling in Mammary Epithelial Cells

Nuclear Janus-Activated Kinase 2/Nuclear Factor 1-C2 Suppresses Tumorigenesis and Epithelial-to-Mesenchymal Transition by Repressing Forkhead Box F1

Nuclear JAK2: Form and Function in Cancer

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