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Gene expression in mammary glands of lactating wild-type or Th-POK-deficient mice.

ABSTRACT: The Th-inducing POK (Th-POK, also known as cKrox or ZBTB7B) transcription factor is a key regulator of lineage commitment of immature T cell precursors. It is yet unclear the physiological functions of Th-POK besides helper T cell differentiation. We found that Th-POK is restrictedly expressed in the luminal epithelial cells in the mammary glands. Th-POK is not required for mammary gland development in puberty and alveologenesis in pregnancy. Th-POK-deficient mice are defective in secretory activation upon parturition with large cellular lipid droplets retained within alveolar epithelial cells. We compared microarray gene expression in mammary glands of lactating wild-type or Th-POK-deficient mice. We show that Th-POK directly regulates expression of insulin receptor substrate-1 (IRS-1) and insulin-induced Akt-mTOR-SREBP signaling. Th-POK deficiency compromises IRS-1 expression and Akt-mTOR-SREBP signaling in the mammary glands. Thus, Th-POK function as an important regulator of insulin signaling in mammary gland lactation.

ORGANISM(S): Mus musculus

PROVIDER: GSE97566 | GEO | 2018/02/06

REPOSITORIES: GEO

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Project description:Sonntag2012 - mTOR model - IRS dependent regulation of AMPK by insulin TSC1-TSC2 complex has two states: 1) active (TSC1_TSC2_pS1387), regulated by AMPK_pT172; 2) inactive (TSC1_TSC2_pT1462) regulated by Akt_pT308. Particularly, mTORC1 is inhibited by TSC1_TSC2 in active state. AMPK is activated at T172 by the species IRS1_p activated by the insulin receptor upon insulin stimulation. Consequently, AMPK_pT172 is inhibited by mTORC1_pS2448 indirectly by the p70-S6K-negative feedback loop. This model is described in the article: A modelling-experimental approach reveals insulin receptor substrate (IRS)-dependent regulation of adenosine monosphosphate-dependent kinase (AMPK) by insulin. Sonntag AG, Dalle Pezze P, Shanley DP, Thedieck K. FEBS J. 2012 Sep; 279(18): 3314-3328 Abstract: Mammalian target of rapamycin (mTOR) kinase responds to growth factors, nutrients and cellular energy status and is a central controller of cellular growth. mTOR exists in two multiprotein complexes that are embedded into a complex signalling network. Adenosine monophosphate-dependent kinase (AMPK) is activated by energy deprivation and shuts off adenosine 5'-triphosphate (ATP)-consuming anabolic processes, in part via the inactivation of mTORC1. Surprisingly, we observed that AMPK not only responds to energy deprivation but can also be activated by insulin, and is further induced in mTORC1-deficient cells. We have recently modelled the mTOR network, covering both mTOR complexes and their insulin and nutrient inputs. In the present study we extended the network by an AMPK module to generate the to date most comprehensive data-driven dynamic AMPK-mTOR network model. In order to define the intersection via which AMPK is activated by the insulin network, we compared simulations for six different hypothetical model structures to our observed AMPK dynamics. Hypotheses ranking suggested that the most probable intersection between insulin and AMPK was the insulin receptor substrate (IRS) and that the effects of canonical IRS downstream cues on AMPK would be mediated via an mTORC1-driven negative-feedback loop. We tested these predictions experimentally in multiple set-ups, where we inhibited or induced players along the insulin-mTORC1 signalling axis and observed AMPK induction or inhibition. We confirmed the identified model and therefore report a novel connection within the insulin-mTOR-AMPK network: we conclude that AMPK is positively regulated by IRS and can be inhibited via the negative-feedback loop. This model is hosted on BioModels Database and identified by: BIOMD0000000580. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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Gene expression in mammary glands of lactating wild-type or Th-POK-deficient mice.

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