Tissue-Specific Induction of SOCS Gene Expression by PRL

Abstract

The mechanisms whereby tissue sensitivity to PRL is controlled are not well understood. Here we report that expression of mRNA and protein for members of the SOCS/CIS/JAB family of cytokine signaling inhibitors is increased by PRL administration in ovary and adrenal gland of the lactating rat deprived of circulating PRL and pups for 24 h but not in mammary gland. Moreover, suckling increases SOCS mRNA in the ovary but not in the mammary gland of pup-deprived rats. Deprivation of PRL and pups for 48 h allows the mammary gland to induce SOCS genes in response to PRL administration, and this is associated with a decrease in basal SOCS-3 mRNA and protein expression to the level seen in other tissues, suggesting that SOCS-3 induced refractoriness related to filling of the gland. In reporter assays, SOCS-1, SOCS-3, and CIS, but not SOCS-2, are able to inhibit transactivation of the STAT 5-responsive beta-lactoglobulin promoter in transient transfection assays. Moreover, suckling results in loss of ovarian and adrenal responsiveness to PRL administered 2 h after commencement of suckling, as determined by STAT 5 gel shift assay. Immunohistochemistry was used to localize the cellular sites of SOCS-3 and CIS protein expression in the ovary and adrenal gland. We propose that induced SOCS-1, SOCS-3, and CIS are actively involved in the cellular inhibitory feedback response to physiological PRL surges in the corpus luteum and adrenal cortex during lactation, but after pup withdrawal, the mammary gland is rendered unresponsive to PRL by increased levels of SOCS-3.

Suppressor of cytokine signalling gene expression is elevated in breast carcinoma

“…These are also known to induce substantial SOCS-1 -3 and CIS gene expression (Adams et al, 1998;Tam et al, 2001). The presence of GH and PRL receptors in both epithelial and stromal cells has been previously shown in the normal human breast and in various benign and malignant human breast disorders (Clevenger et al, 1995;Mertani et al, 1998;Gebre-Medhin et al, 2001).…”

“…for 20 min. Protein samples (100 mg) were immunoblotted as previously described (Tam et al, 2001). After semidry transfer, nitrocellulose membranes were blocked with TBS (pH 8.0) containing 5% skim milk, 0.1% Tween 20 and probed with goat anti-CIS antibody (1 : 250, Santa Cruz Biotechnology; cat.…”

“…Prolactin receptor mRNA was expressed in all but one of the transformed lines and not in the two control lines, but the level of prolactin receptor expression did not correlate with the level of CIS mRNA across these lines ( Figure 5). It is possible that endogenous or exogenous prolactin could elevate CIS transcripts in these lines, but the lack of correlation between CIS transcript levels and expression of other SOCS transcripts argues against this, given that prolactin is able to induce SOCS-1,-3 and CIS transcripts in mammary tisue (Tam et al, 2001). …”

“…These inhibitory regulators not only attenuate the signal from the activated cytokine receptor itself, but can also decrease cell sensitivity to other cytokines and hormones, such as insulin (Emanuelli et al, 2000). Thus, prolactin, the major trophic cytokine for the breast, is known to rapidly induce SOCS-1 -3 and CIS, and this results in loss of sensitivity to subsequent prolactin challenge (Tam et al, 2001). SOCS-1 has been shown to be critical for preventing interferon g (IFNg)-mediated growth arrest of M-1 myeloid cells (Sakamoto et al, 1998), and overexpression of SOCS-1 or SOCS-3 in breast cancer lines inhibits the antiviral and antiproliferative ability of IFNg (Song and Shuai, 1998).…”

Seasonal effects of central leptin infusion and prolactin treatment on pituitary SOCS-3 gene expression in ewes

“…In vivo studies have shown that PRL stimulated SOCS-3 expression in murine liver (Pezet et al 1999) and adipose tissue (Ling & Billig 2001) as well as in rat ovaries, mammary glands and adrenal glands (Tam et al 2001). In addition, PRL stimulated SOCS-3 expression in murine adipose tissue in vitro (Ling & Billig 2001).…”