Interleukin-1 alpha mediates the growth proliferative effects of transforming growth factor-beta in p21 null MCF-10A human mammary epithelial cells

The effects of transforming growth factor beta (TGF-beta) were studied in closely related human mammary epithelial cells (HMEC), both finite-life-span 184 cells and immortal derivatives, 184A1S, and 184A1L5R, which differ in their cell cycle responses to TGF-beta but express type I and type II TGF-beta receptors and retain TGF-beta induction of extracellular matrix. The arrest-resistant phenotype was not due to loss of cyclin-dependent kinase (cdk) inhibitors. TGF-beta was shown to regulate p15INK4B expression at at least two levels: mRNA accumulation and protein stability. In TGF-beta-arrested HMEC, there was not only an increase in p15 mRNA but also a major increase in p5INK4B protein stability. As cdk4- and cdk6-associated p15INK4B increased during TGF-beta arrest of sensitive cells, there was a loss of cyclin D1, p21Cip1, and p27Kip1 from these kinase complexes, and cyclin E-cdk2-associated p27Kip1 increased. In HMEC, p15INK4B complexes did not contain detectable cyclin. p15INK4B from both sensitive and resistant cells could displace in vitro cyclin D1, p21Cip1, and p27Kip1 from cdk4 isolated from sensitive cells. Cyclin D1 could not be displaced from cdk4 in the resistant 184A1L5R cell lysates. Thus, in TGF-beta arrest, p15INK4B may displace already associated cyclin D1 from cdks and prevent new cyclin D1-cdk complexes from forming. Furthermore, p27Kip1 binding shifts from cdk4 to cyclin E-cdk2 during TGF-beta-mediated arrest. The importance of posttranslational regulation of p15INK4B by TGF-beta is underlined by the observation that in TGF-beta-resistant 184A1L5R, although the p15 transcript increased, p15INK4B protein was not stabilized and did not accumulate, and cyclin D1-cdk association and kinase activation were not inhibited.

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Actions of the soy phytoestrogen genistein in models of human chronic disease: potential involvement of transforming growth factor β

Biochemical Society Transactions ◽

10.1042/bst0290216 ◽

2001 ◽

Vol 29 (2) ◽

pp. 216-222 ◽

Cited By ~ 26

Author(s):

H. Kim ◽

J. Xu ◽

Y. Su ◽

H. Xia ◽

L. Li ◽

...

Keyword(s):

Growth Factor ◽

Epithelial Cells ◽

Transforming Growth Factor ◽

Mammary Epithelial Cells ◽

Hormone Replacement ◽

Transforming Growth Factor Β ◽

Mammary Epithelial ◽

Primate Model ◽

Human Mammary Epithelial Cells ◽

Human Mammary Epithelial

The structural similarity, but non-identity, between 17β-oestradiol and the soy phytoestrogen genistein suggests that the two compounds will have actions that may be identical in some target biological systems, but different in others. Epidermal growth factor (EGF)-stimulated proliferation of human mammary epithelial cells (that do not express the oestrogen receptor) was significantly suppressed at genistein concentrations (5–10μM) that are attainable physiologically. Others have shown previously that transforming growth factor β (TGFβ) has similar growth-inhibitory effects on human cells. Analysis of the conditioned medium of human mammary epithelial cells exposed to genistein plus EGF showed increased levels of TGFβ relative to those in the medium of cells exposed to EGF or genistein alone. Related experiments in a primate model of menopause demonstrated that ingestion of soy containing isoflavones was correlated with the suppression of neurodegeneration-relevant phosphorylation of the microtubule-associated protein tau, while intake of Premarin (a hormone replacement therapy that is commonly prescribed for women) was not correlated. The results discussed here indicate that genistein, and probably other related phytoestrogens, have pleiotropic actions, some of which may involve TGFβ activity.

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