Transcriptional Synergy between LIM-Homeodomain Proteins and Basic Helix-Loop-Helix Proteins: the LIM2 Domain Determines Specificity

Johnson, Jeffrey D.; Zhang, W; Rudnick, A; Rutter, William J.; German, Michael S.

doi:10.1128/mcb.17.7.3488

Cited by 89 publications

(66 citation statements)

References 38 publications

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“…We have previously described a similar effect of NLI in which NLI disrupted the transcriptional synergy between Lmx1.1 and E47 from the rat insulin I mini-enhancer by competing with E47 for direct interaction with the LIM domains of Lmx1.1 (16,40). In addition, it is possible that phosphorylation of the Isl1 C terminus blocks the interaction between Isl1 and Lhx3, further promoting the formation of NLI-dependent complexes.…”

Section: Discussionmentioning

confidence: 88%

The Nuclear LIM Domain Interactor NLI Mediates Homo- and Heterodimerization of LIM Domain Transcription Factors

Jurata¹,

Pfaff²,

Gill³

1998

Journal of Biological Chemistry

153

102

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The LIM domain transcription factor family includes LIM homeodomain proteins, which consist of two N-terminal LIM domains and a C-terminal DNA-binding homeodomain, and LIM-only (LMO) 1 proteins, which contain little more than two LIM domains (for review see Refs. 1 and 2). Gene deletion studies in mice have revealed that both LIM homeodomain and LMO proteins are essential for embryonic viability, as well as for the development of motor neurons and interneurons, the pancreas, the pituitary, the head, and erythrocytes (3-7). Most LIM domain transcription factors have limited patterns of expression, but all have been shown to be expressed within subregions of the developing nervous system (8 -13).Studies investigating the role of LIM homeodomain proteins in neuronal development have largely focused on motor neuron differentiation, for which expression of the LIM homeobox gene Isl1 is required (3). Along with Isl1, the LIM homeodomain proteins Isl2, Lhx1, and Lhx3 show overlapping patterns of expression in developing motor neurons, which are located in the ventral, postmitotic region of the spinal cord (8). Furthermore, the combinatorial expression patterns of these four proteins in subsets of developing motor neurons correlates with the future organization of these neurons into specific motor columns that innervate distinct targets. Because the expression of these factors precedes the organization of motor columns and axonal migration, the combinatorial pattern of LIM homeodomain gene expression appears to play a functional role in the specification of motor neuron identity. The combinatorial expression of other LIM domain transcription factors may similarly dictate neuronal identity and axonal pathway selection in the development of interneurons and commissural neurons, which are located dorsal to the motor neurons in the neural tube, and of sensory neurons located in the dorsal root ganglia. Indeed, the Drosophila LIM homeodomain protein apterous has been demonstrated to mediate axonal pathway selection of embryonic interneurons (10). It has been proposed that LIM domain transcription factors regulate the expression of cell surface molecules involved in axon fasciculation and pathfinding (10, 14). However, neuron-specific gene targets for the LIM homeodomain proteins have not yet been identified, and little is understood about the biochemical basis for the proposed LIM homeodomain combinatorial code for neuronal identity.NLI (Ldb1), a recently identified nuclear protein, binds with high affinity to the LIM domains of all LIM homeodomain and nuclear LMO proteins but not to cytoplasmic LIM domaincontaining proteins (15-18). Although widely expressed, highest levels of NLI protein are found in postmitotic cells of the embryonic neural tube and in other regions of the developing central nervous system, significantly overlapping the expression patterns of many LIM domain transcription factors (15). The functional domains of NLI include an N-terminal homodimerization domain and a C-terminal LIM interaction domain (16)....

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Section: Discussionmentioning

confidence: 88%

The Nuclear LIM Domain Interactor NLI Mediates Homo- and Heterodimerization of LIM Domain Transcription Factors

Jurata¹,

Pfaff²,

Gill³

1998

Journal of Biological Chemistry

153

102

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“…Expression of Bacterial His 6 -tagged Recombinant Proteins-The cDNAs encoding hamster E47 (the hamster protein is usually called Pan1), mouse Beta2 (also known as NeuroD1), hamster PDX-1 (PDX-1 is also known as IPF-1, IDX-1, and STF-1), and hamster Lmx1.1 (46,47) were subcloned into pRSET-His 6 (Invitrogen). His 6 -tagged proteins were purified as described (48).…”

Section: Methodsmentioning

confidence: 99%

Regulation of Insulin Gene Transcription by ERK1 and ERK2 in Pancreatic β Cells

Khoo

Griffen

Xia

et al. 2003

Journal of Biological Chemistry

146

142

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We show that the mitogen-activated protein kinases ERK1/2 are components of the mechanism by which glucose stimulates insulin gene expression. ERK1/2 activity is required for glucose-dependent transcription from both the full-length rat insulin I promoter and the glucose-sensitive isolated E2A3/4 promoter element in intact islets and ␤ cell lines. Dominant negative ERK2 and MEK inhibitors suppress glucose stimulation of the rat insulin I promoter and the E2A3/4 element. Overexpression of ERK2 is sufficient to stimulate transcription from the E2A3/4 element. The glucose-induced response is dependent upon ERK1/2 phosphorylation of a subset of transcription factors that include Beta2 (also known as NeuroD1) and PDX-1. Phosphorylation increases their functional activity and results in a cumulative transactivation of the promoter. Thus, ERK1/2 act at multiple points to transduce a glucose signal to insulin gene transcription.

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“…In support of this possibility, the Isl-1 knockout mouse was found to have no dorsal pancreatic mesenchyme or differentiated islet cells, despite normal expression of Pdx-1 in these animals (7). In addition, Isl-1, which is one of the LIM homeodomain proteins, may synergistically activate the insulin mRNA transcription rate through binding with basic helix-loophelix proteins (35,36). Together, these experiments and along with our results suggest that Isl-1 is a key factor for the differentiation of cells that produce insulin.…”

Section: Pdx-1 and Isl-1 Enable Enterocytes To Produce Insulinmentioning

confidence: 99%

Combined Expression of Pancreatic Duodenal Homeobox 1 and Islet Factor 1 Induces Immature Enterocytes to Produce Insulin

et al. 2002

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Immature rat intestinal stem cells (IEC-6) given the ability to express the transcription factor, pancreatic duodenal homeobox 1 (Pdx-1), yielded YK cells. Although these cells produced multiple enteroendocrine hormones, they did not produce insulin. Exposure of YK cells to 2 nmol/l betacellulin yielded BYK cells that showed the presence of insulin expression in cytoplasm and that secreted insulin into culture media. By examining the mechanism of differentiation in BYK cells, we found that another transcription factor, islet factor 1 (Isl-1) was newly expressed with the disappearance of Pax-6 expression in those cells after exposure to betacellulin. These results indicated that combined expression of Pdx-1 and Isl-1 in IEC-6 cells was required for the production of insulin. In fact, overexpression of both Pdx-1 and Isl-1 in IEC-6 cells (Isl-YK-12, -14, and -15 cells) gave them the ability to express insulin without exposure to betacellulin. Furthermore, implantation of the Isl-YK-14 cells into diabetic rats reduced the animals' plasma glucose levels; glucose levels dropped from 19.4 to 16.9 mmol/l 1 day after the injection of cells. As expected, the plasma insulin concentrations were 2.7 times higher in the diabetic rats injected with Isl-YK-14 cells compared to in controls. In summary, our results indicated that immature intestinal stem cells can differentiate into insulin-producing cells given the ability to express the transcription factors Pdx-1 and Isl-1.

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Transcriptional Synergy between LIM-Homeodomain Proteins and Basic Helix-Loop-Helix Proteins: the LIM2 Domain Determines Specificity

Cited by 89 publications

References 38 publications

The Nuclear LIM Domain Interactor NLI Mediates Homo- and Heterodimerization of LIM Domain Transcription Factors

The Nuclear LIM Domain Interactor NLI Mediates Homo- and Heterodimerization of LIM Domain Transcription Factors

Regulation of Insulin Gene Transcription by ERK1 and ERK2 in Pancreatic β Cells

Combined Expression of Pancreatic Duodenal Homeobox 1 and Islet Factor 1 Induces Immature Enterocytes to Produce Insulin

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