Streptozotocin-induced diabetes in mice lacking αβ T cells

Elliott, James I.; Dewchand, Hamlata; Altmann, Daniel M.

doi:10.1046/j.1365-2249.1997.4241319.x

Cited by 37 publications

(37 citation statements)

References 38 publications

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“…NOD-scid mice received five i.p. injections of streptozotocin (40 g͞g body weight) every other day, according to published procedures (19,20). The blood glucose levels were monitored daily by using an Accu-CHEK glucose detector (Roche Diagnostics).…”

Section: Measurement Of Insulin Content and Secretion By Immunoprecipmentioning

confidence: 99%

In vitro trans-differentiation of adult hepatic stem cells into pancreatic endocrine hormone-producing cells

Yang

Hatch

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

461

306

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Although organ-specific stem cells possess plasticity that permit differentiation along new lineages, production of endocrine pancreas and insulin-secreting ␤ cells from adult nonpancreatic stem cells has not been demonstrated. We present evidence that highly purified adult rat hepatic oval ''stem'' cells, which are capable of differentiation to hepatocytes and bile duct epithelium, can transdifferentiate into pancreatic endocrine hormone-producing cells when cultured in a high-glucose environment. These differentiated cells can self-assemble to form three-dimensional islet cell-like clusters that express pancreatic islet cell differentiation-related transcripts detectable by reverse transcription-PCR͞nested PCR (e.g., PDX-1, PAX-4, PAX-6, Nkx2.2 and Nkx6.1, insulin I, insulin II, glucose transporter 2, and glucagon) and islet-specific hormones detectable by immunocytochemistry (e.g., insulin, glucagon, and pancreatic polypeptide). In addition, these cells concomitantly lose expression of the hepatocyte protein Hep-par. When stimulated with glucose, these cells synthesize and secrete insulin, a response enhanced by nicotinamide. In a pilot study, the oval cell-derived islet cell-like clusters displayed the ability to reverse hyperglycemia in a diabetic NOD-scid mouse. These results indicate that primary adult liver stem cells can differentiate in a nonlineage-restricted manner. Trans-differentiation into endocrine pancreas could have significant implications for future therapies of diabetes.

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Section: Measurement Of Insulin Content and Secretion By Immunoprecipmentioning

confidence: 99%

In vitro trans-differentiation of adult hepatic stem cells into pancreatic endocrine hormone-producing cells

Yang

Hatch

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

461

306

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“…These peptides, which arise from proteolytic cleavage in the cytosol, are delivered to the ER by the action of a protein complex referred to as the transporter associated with antigen processing or TAP (reviewed by Elliott, 1997). TAP consists of two protein subunits, TAP1 and TAP2, which are encoded by separate genes located in the MHC class II cluster of the MHC.…”

mentioning

confidence: 99%

Transcriptional regulation of the major histocompatibility complex (MHC) class I heavy chain, TAP1 and LMP2 genes by the human papillomavirus (HPV) type 6b, 16 and 18 E7 oncoproteins

2000

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We have examined the possibility that the E7 proteins of the high-risk human papillomavirus (HPV) type 16 and 18 and the oncogenic adenovirus (Ad) type 12 E1A protein share the ability to down-regulate the expression of components of the antigen processing and presentation pathway, as a common strategy in the evasion of immune surveillance during the induction of cell transformation. Expression of the HPV 18 E7 oncoprotein, like Ad 12 E1A, resulted in repression of the major histocompatibility complex (MHC) class I heavy chain promoter, as well as repression of a bidirectional promoter that regulates expression of the genes encoding the transporter associated with antigen processing subunit 1 (TAP1) and a proteasome subunit, low molecular weight protein 2 (LMP2). HPV 16 E7 also caused a reduction in class I heavy chain promoter activity, however it did not have any signi®cant e ect on the activity of the bidirectional promoter. Interestingly, expression of the low-risk HPV 6b E7 protein resulted in an increase in MHC class I heavy chain promoter activity, while repressing the TAP1/LMP2 promoter. Interference with the class I pathway could also explain the ability of low-risk HPVs in inducing benign lesions. Oncogene (2000) 19, 4930 ± 4935.

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“…TAP1 and TAP2 form a heterodimeric complex in the membrane of the endoplasmic reticulum and proximal Golgi that provides antigenic peptides to newly synthesized and assembling MHC class I molecules (12). TAP is essential for MHC class I-restricted antigen presentation, as demonstrated by absent or low MHC class I expression in TAP-deficient mice and cell lines (13).…”

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confidence: 99%

Distinct Functions of the ATP Binding Cassettes of Transporters Associated with Antigen Processing

Saveanu

Daniel

Endert

2001

Journal of Biological Chemistry

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The transporters associated with antigen processing (TAP1/TAP2) provide peptides to MHC class I molecules in the endoplasmic reticulum. Like other ATP-binding cassette proteins, TAP uses ATP hydrolysis to power transport. We have studied peptide binding to as well as translocation by TAP proteins with mutations in the Walker A and B sequences that are known to mediate ATP binding and hydrolysis. We show that a mutation in the TAP1 Walker B sequence reported to abrogate class I expression by a lung tumor does not affect ATP binding affinity, suggesting a defect restricted to ATP hydrolysis. This mutation reduces peptide transport by only 50%, suggesting that TAP function can be highly limiting for antigen presentation in non-lymphoid cells. Single substitutions in Walker A sequences (TAP1K544A, TAP2K509A), or their complete replacements, abrogate nucleotide binding to each subunit. Although all of these mutations abrogate peptide transport, they reveal distinct roles for nucleotide binding to the two transporter subunits in TAP folding and in regulation of peptide substrate affinity, respectively. Alteration of the TAP1 Walker A motif can have strong effects on TAP1 and thereby TAP complex folding. However, TAP1 Walker A mutations compatible with correct folding do not affect peptide binding. In contrast, abrogation of the TAP2 nucleotide binding capacity has little or no effect on TAP folding but eliminates peptide binding to TAP at 37°C in the presence of nucleotides. Thus, nucleotide binding to TAP2 but not to TAP1 is a prerequisite for peptide binding to TAP. Based on these results, we propose a model in which nucleotide and peptide release from TAP are coupled and followed by ATP binding to TAP2, which induces high peptide affinity and initiates the transport cycle.The transporters associated with antigen processing (TAP) 1 belong to the family of ATP binding cassette (ABC) transporters, a large group of proteins that use energy provided by nucleotide triphosphates to translocate a vast variety of substrates across intracellular or cell surface membranes (1). All ABC transporters possess two transmembrane domains, each generally composed of six membrane-spanning segments, and two nucleotide binding domains (NBDs) with primary sequence homology across the protein family. Whereas substrate interaction is generally thought to involve the transmembrane domains, the NBDs bind and hydrolyze ATP. Both of the latter events have been shown to lead to conformational changes that upon transmission to substrate binding domains in an undefined fashion result in substrate translocation (2).Given the important role of ABC transporters in diseases such as mucoviscidosis or cancer, the mechanism of substrate transport has been subject to intense scrutiny. Mutagenesis studies and crystallographic analysis of HisP and MalK, the NBDs of bacterial histidine and maltose transporters, respectively, have elucidated the role of several conserved sequence motifs contained in ABC transporter NBDs (3, 4). Thus, the Walker A consensus s...

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Streptozotocin-induced diabetes in mice lacking αβ T cells

Cited by 37 publications

References 38 publications

In vitro trans-differentiation of adult hepatic stem cells into pancreatic endocrine hormone-producing cells

In vitro trans-differentiation of adult hepatic stem cells into pancreatic endocrine hormone-producing cells

Transcriptional regulation of the major histocompatibility complex (MHC) class I heavy chain, TAP1 and LMP2 genes by the human papillomavirus (HPV) type 6b, 16 and 18 E7 oncoproteins

Distinct Functions of the ATP Binding Cassettes of Transporters Associated with Antigen Processing

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