Activation of Stat5a and Stat5b by tyrosine phosphorylation is tightly linked to mammary gland differentiation.

Abstract

Signal transducer and activator of transcription (Stat)5 was originally identified as a mammary gland factor (MGF) that binds to promoter sequences of milk protein genes and activates their transcription. We have generated isoform-specific antibodies against Stat5a or Stat5b and show that both isoforms are present in similar amounts at the protein level in mammary tissues of virgin, pregnant, lactating, and involuting mice. In contrast, Stat5 phosphorylation is very low in immature virgins, rises sharply during late pregnancy, and declines rapidly during involution. Upon phosphorylation, Stat5a and Stat5b form homo- and heterodimers. The induction of Stat5 phosphorylation during late pregnancy correlates with the transcriptional activation of milk protein genes. Using electrophoretic mobility shift assay and supershift analysis, we demonstrated that the DNA-binding activity detected during lactation is composed of both Stat5a and Stat5b, but not of other STATs. The hypothesis that Stat5 is directly involved in mammary cell differentiation was tested in estrous cycle and in transgenic mice with impaired mammary development. Transient differentiation of mammary alveolar cells and milk protein gene expression during estrus in virgin female mice coincide with transient Stat5 phosphorylation. Impaired mammary development and very low levels of milk protein gene expression in mice carrying the truncated form of the cell fate protein Int3 correlated with reduced phosphorylation and heterodimer formation.

Socs 3 modulates the activity of the transcription factor Stat3 in mammary tissue and controls alveolar homeostasis

“…Starting after day 8 of pregnancy, the levels of Stat5a increase sharply followed by phosphorylation and nuclear localization. Stat3 activation levels are low during pregnancy and increase dramatically only at the onset of involution (Liu et al, 1996). In control tissue, phosphorylated Stat3 was not detected at day 13 of pregnancy ( Fig.…”

“…Although Stat3 is present throughout puberty, pregnancy, lactation, and involution, its activation is largely confined to the process of involution (Liu et al, 1996) where it controls the death and remodeling of mammary epithelium (Chapman et al, 1999;Humphreys et al, 2002). Maintaining Stat3 in a quiescent state during pregnancy and lactation could be important to ensure proliferation and differentiation of mammary epithelium instead of initiating apoptosis.…”

“…Placental lactogens and prolactin activate the transcription factors Stat5a and Stat5b (Liu et al, 1996), which are essential for alveolar proliferation and differentiation during pregnancy (Liu et al, 1997;Miyoshi et al, 2001;Cui et al, 2004). Moreover, Stat5a/b are required for the maintenance of alveolar function during pregnancy (Cui et al, 2004).…”

“…Stat3 and Stat5a/b are present throughout mammary development in their latent forms (Liu et al, 1996) and their activity is confined to specific periods of the gland's developmental cycles. Members of the SOCS family of proteins control cytokine signaling through the inhibition of STAT activation (Yoshimura et al, 2005).…”

Mammary-derived signals activate programmed cell death during the first stage of mammary gland involution

“…Importantly, this phase of PCD is p53-independent (8). Changes in activity of two Stat family members accompany mammary gland involution: decreased activity of the prolactinsignaling molecules Stat5a and Stat5b (13,14) and activation of Stat3 (14).…”