Signaling Differences from the A and B Isoforms of the Insulin Receptor (IR) in 32D Cells in the Presence or Absence of IR Substrate-1

Sciacca, Laura; Prisco, Marco di; Wu, An Guo; Belfiore, Antonino; Vigneri, Riccardo; Baserga, Renato

doi:10.1210/en.2002-0136

Cited by 88 publications

(70 citation statements)

References 68 publications

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“…Lower panel: The abundance of pS2 and 36B4 mRNAs in COS-7 cells transfected with different plasmids was detected by RT-PCR, as described in Materials and methods Nuclear IRS-1/ERa interactions C Morelli et al tion of IRS-1 is blocked with ICI and does not occur in ERa-negative cells; (3) nuclear IRS-1 interacts with ERa; (4) nuclear IRS-1 is corecruited with ERa to the ERE-containing pS2 promoter; and (5) the presence of IRS-1 decreases ERa transcription at ERE promoters. Nuclear localization of IRS-1 has recently been described in different cellular systems (Lassak et al, 2002;Prisco et al, 2002;Sun et al, 2003;Tu et al, 2002;Sciacca et al, 2003). The mechanism by which IRS-1 enters cell nucleus is still not clear.…”

Section: Discussionmentioning

confidence: 99%

“…Several rigorously controlled studies demonstrated that nuclear IRS-1 can be found in cells transformed by oncogenic proteins, for example, T antigens of the JCV (Lassak et al, 2002) and SV40 viruses, and v-src (Tu et al, 2002). Nuclear translocation of IRS-1 has also been described in mouse embryo fibroblasts stimulated with IGF-I (Tu et al, 2002;Sun et al, 2003), 32D murine cells (Sciacca et al, 2003), osteoblasts (Seol and Kim, 2003), and hepatocytes (Boylan and Gruppuso, 2002). The mechanism by which IRS-1 is targeted to the nucleus is unknown.…”

Section: Introductionmentioning

confidence: 99%

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Nuclear insulin receptor substrate 1 interacts with estrogen receptor α at ERE promoters

et al. 2004

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Insulin receptor substrate 1 (IRS-1) is a major signaling molecule activated by the insulin and insulin-like growth factor I receptors. Recent data obtained in different cell models suggested that in addition to its conventional role as a cytoplasmic signal transducer, IRS-1 has a function in the nuclear compartment. However, the role of nuclear IRS-1 in breast cancer has never been addressed. Here we report that in estrogen receptor a (ERa)-positive MCF-7 cells, (1) a fraction of IRS-1 was translocated to the nucleus upon 17-b-estradiol (E2) treatment; (2) E2-dependent nuclear translocation of IRS-1 was blocked with the antiestrogen ICI 182,780; (3) nuclear IRS-1 colocalized and co-precipitated with ERa; (4) the IRS-1:ERa complex was recruited to the E2-sensitive pS2 gene promoter. Notably, IRS-1 interaction with the pS2 promoter did not occur in ERa-negative MDA-MB-231 cells, but was observed in MDA-MB-231 cells retransfected with ERa. Transcription reporter assays with E2-sensitive promoters suggested that the presence of IRS-1 inhibits ERa activity at estrogen-responsive elementcontaining DNA. In summary, our data suggested that nuclear IRS-1 interacts with ERa and that this interaction might influence ERa transcriptional activity.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Nuclear insulin receptor substrate 1 interacts with estrogen receptor α at ERE promoters

et al. 2004

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“…In pancreatic -cells, IR-A regulates insulin gene expression and IR-B does the same with -glucokinase but using different classes of phosphatidylinositol 3-kinase (PI3K) (Leibiger et al 2001). In 32D cells, a murine hematopoietic cell line, IR-A sends mitogenic, antiapoptotic signals in response to insulin-like growth factor-II, whereas IR-B is more effective in inducing differentiation (Sciacca et al 2003). …”

Section: Introductionmentioning

confidence: 99%

Differential gene expression of insulin receptor isoforms A and B and insulin receptor substrates 1, 2 and 3 in rat tissues: modulation by aging and differentiation in rat adipose tissue

Serrano

Villar²,

Martı́nez

et al. 2005

Journal of Molecular Endocrinology

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The insulin receptor (IR) occurs as two alternatively spliced isoforms, IR-A (exon 11−) and IR-B (exon 11+), which exhibit functional differences and are expressed in a tissue-specific manner. The IR substrate (IRS) proteins 1, 2 and 3 also differ in function and tissue distribution. Here we show the differential gene expression of IRs and IRSs in several rat target tissues of insulin action. IR-B is significantly higher than IR-A in epididymal white adipose tissue and adipogenesis induces a shift in the alternatively spliced species of IR from the A to the B isoform. Moreover, since aging in the rat is associated with the development of insulin resistance we looked for alterations of expression of these proteins in adipocytes from old rats. Our results reveal that there is a specific decrease in the expression of the IR-B isoform, as well as both mRNA and protein levels of IR, IRS-1 and IRS-3 being significantly decreased, in epididymal adipose tissue from old compared with adult rats. It is concluded that the down-regulation of early components of the insulin transduction pathway in a primary insulin target tissue could be related to the insulin resistance of aging.

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“…The experiments in Fig. 1 were done on cells 48 hours after shifting from IL-3 to the respective ligands (IGF-I for the IGF-IR and insulin for the InR), when the cells are still proliferating (19,20). Not surprisingly, the difference disappears when the cells are shifted to the wrong ligand (i.e., InR/…”

Section: Resultsmentioning

confidence: 99%

“…We used three 32D-derived cell lines for these studies: 32D IGF-IR cells that do not express IRS-1, 32D IGF-IR/IRS-1 cells, and 32D InR/IRS-1, described in detail in previous articles (19,20). 32D InR cells not expressing IRS-1 could not be included in these experiments as they die rapidly (within 16 hours) when shifted to insulin.…”

Section: Introductionmentioning

confidence: 99%

A Mechanism for Cell Size Regulation by the Insulin and Insulin-Like Growth Factor-I Receptors

Sun

Tu²,

Baserga³

2006

Cancer Research

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Deletion of the type 1 insulin-like growth factor receptor (IGF-IR) or of the insulin receptor substrate-1 (IRS-1) genes in animals causes a 50% reduction in body size at birth. Decrease in body size is due to both a decreased number of cells and a decreased cell size. Deletion of the insulin receptor (InR) genes results in mice that are normal in size at birth. We have used 32D-derived myeloid cells to study the effect of IGF-IR and InR signaling on cell size. 32D cells expressing the IGF-IR and IRS-1 are almost twice as large as 32D cells expressing the InR and IRS-1. A mechanism for the difference in size is provided by the levels of the upstream binding factor 1 (UBF1), a nucleolar protein that participates in the regulation of RNA polymerase I activity and rRNA synthesis and therefore cell size. When shifted to the respective ligands, UBF1 levels decrease in cells expressing the InR and IRS-1, whereas they remain stable in cells expressing the IGF-IR and IRS-1. The expression of the IGF-IR and IRS-1 is crucial to the stability of UBF1. (Cancer Res 2006; 66(23): 11106-9)

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Signaling Differences from the A and B Isoforms of the Insulin Receptor (IR) in 32D Cells in the Presence or Absence of IR Substrate-1

Cited by 88 publications

References 68 publications

Nuclear insulin receptor substrate 1 interacts with estrogen receptor α at ERE promoters

Nuclear insulin receptor substrate 1 interacts with estrogen receptor α at ERE promoters

Differential gene expression of insulin receptor isoforms A and B and insulin receptor substrates 1, 2 and 3 in rat tissues: modulation by aging and differentiation in rat adipose tissue

A Mechanism for Cell Size Regulation by the Insulin and Insulin-Like Growth Factor-I Receptors

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