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M Nilsen-Hamilton

Publications and source records attributed to M Nilsen-Hamilton.

At least 19 recordsLinked to original sources
PubMed2001

Mathematical modeling of capillary formation and development in tumor angiogenesis: penetration into the stroma.

The purpose of this paper is to present a mathematical model for the tumor vascularization theory of tumor growth proposed by Judah Folkman in the early 1970s and subsequently established experimentally by him and his coworkers [Ausprunk, D. H. and J. Folkman (1977) Migration and proliferation of endothelial cells in performed and newly formed blood vessels during tumor angiogenesis, Microvasc Res., 14, 53-65; Brem, S., B. A. Preis, ScD. Langer, B. A. Brem and J. Folkman (1997) Inhibition of neovascularization by an extract derived from vitreous Am. J. Opthalmol., 84, 323-328; Folkman, J. (1976) The vascularization of tumors, Sci. Am., 234, 58-64; Gimbrone, M. A. Jr, R. S. Cotran, S. B. Leapman and J. Folkman (1974) Tumor growth and neovascularization: an experimental model using the rabbit cornea, J. Nat. Cancer Inst., 52, 413-419]. In the simplest version of this model, an avascular tumor secretes a tumor growth factor (TGF) which is transported across an extracellular matrix (ECM) to a neighboring vasculature where it stimulates endothelial cells to produce a protease that acts as a catalyst to degrade the fibronectin of the capillary wall and the ECM. The endothelial cells then move up the TGF gradient back to the tumor, proliferating and forming a new capillary network. In the model presented here, we include two mechanisms for the action of angiostatin. In the first mechanism, substantiated experimentally, the angiostatin acts as a protease inhibitor. A second mechanism for the production of protease inhibitor from angiostatin by endothelial cells is proposed to be of Michaelis-Menten type. Mathematically, this mechanism includes the former as a subcase. Our model is different from other attempts to model the process of tumor angiogenesis in that it focuses (1) on the biochemistry of the process at the level of the cell; (2) the movement of the cells is based on the theory of reinforced random walks; (3) standard transport equations for the diffusion of molecular species in porous media. One consequence of our numerical simulations is that we obtain very good computational agreement with the time of the onset of vascularization and the rate of capillary tip growth observed in rabbit cornea experiments [Ausprunk, D. H. and J. Folkman (1977) Migration and proliferation of endothelial cells in performed and newly formed blood vessels during tumor angiogenesis, Microvasc Res., 14, 73-65; Brem, S., B. A. Preis, ScD. Langer, B. A. Brem and J. Folkman (1997) Inhibition of neovascularization by an extract derived from vitreous Am. J. Opthalmol., 84, 323-328; Folkman, J. (1976) The vascularization of tumors, Sci. Am., 234, 58-64; Gimbrone, M. A. Jr, R. S. Cotran, S. B. Leapman and J. Folkman (1974) Tumor growth and neovascularization: An experimental model using the rabbit cornea. J. Nat. Cancer Inst., 52, 413-419]. Furthermore, our numerical experiments agree with the observation that the tip of a growing capillary accelerates as it approaches the tumor [Folkman, J. (1976) The vascularization of tumors, Sci. Am., 234, 58-64].

Angiogenesis Inducing Agents↗
PubMed2001

Mathematical modeling of the onset of capillary formation initiating angiogenesis.

It is well accepted that neo-vascular formation can be divided into three main stages (which may be overlapping): (1) changes within the existing vessel, (2) formation of a new channel, (3) maturation of the new vessel. In this paper we present a new approach to angiogenesis, based on the theory of reinforced random walks, coupled with a Michaelis-Menten type mechanism which views the endothelial cell receptors as the catalyst for transforming angiogenic factor into proteolytic enzyme in order to model the first stage. In this model, a single layer of endothelial cells is separated by a vascular wall from an extracellular tissue matrix. A coupled system of ordinary and partial differential equations is derived which, in the presence of an angiogenic agent, predicts the aggregation of the endothelial cells and the collapse of the vascular lamina, opening a passage into the extracellular matrix. We refer to this as the onset of vascular sprouting. Some biological evidence for the correctness of our model is indicated by the formation of teats in utero. Further evidence for the correctness of the model is given by its prediction that endothelial cells will line the nascent capillary at the onset of capillary angiogenesis.

Angiogenesis Inducing Agents↗
PubMed2001

Mrp3, a mitogen-regulated protein/proliferin gene expressed in wound healing and in hair follicles.

During cutaneous wound healing, a marked increase in the local expression of growth factors results in increased migration and proliferation of the cells responsible for tissue repair. The mitogen-regulated protein (MRP)/proliferin proteins are growth factors and angiogenesis factors. Here it is demonstrated that Mrp3 is induced in wound edge keratinocytes during cutaneous wound healing and also temporally appears in the outer root sheath of the hair follicle during the late anagen phase of the hair cycle. In cultured keratinocytes, Mrp3 is induced by keratinocyte growth factor, but not by epidermal growth factor or by transforming growth factor type alpha. Transgenic mice, expressing lacZ under the combined control of the cytomegalovirus immediate early enhancer and the Mrp3 flanking sequences, demonstrate wound- and hair cycle-induced transgene expression. These results show that elements within the flanking regulatory sequences of the Mrp3 gene are involved in the activation of Mrp3 in response to these events. The results reported here suggest that MRP3 may participate in wound healing and hair follicle cycle as a growth factor and/or angiogenesis factor.

Animals↗
PubMed2000

A mathematical model for the roles of pericytes and macrophages in the initiation of angiogenesis. I. The role of protease inhibitors in preventing angiogenesis.

In this paper, a simple mathematical model developed in H.A. Levine, B.D. Sleeman, M. Nilsen-Hamilton [J. Math. Biol., in press] to describe the initiation of capillary formation in tumor angiogenesis is extended to include the roles of pericytes and macrophages in regulating angiogenesis. The model also allows for the presence of anti-angiogenic (angiostatic) factors. The model is based on the observation that angiostatin can prevent the degradation of fibronectin in the basal lamina by inhibiting the catalytic action of active proteolytic enzyme. That is, it is proposed that the inhibitor 'deactivates' the protease but that it does not reduce the over all concentration of the protease. It consequently explores the possibility of preventing neovascular capillaries from migrating through the extra-cellular matrix toward the tumor by inhibiting protease action. The model is based on the theory of reinforced random walks coupled with Michaelis-Menten mechanisms which view endothelial cell receptors as the catalysts for transforming both tumor and macrophage derived angiogenic factors into proteolytic enzyme which in turn degrade the basal lamina. A simple catalytic reaction is proposed for the degradation of the basal lamina by the active proteases. A mechanism, in which the angiostatin acts as a protease inhibitor is discussed which has been substantiated experimentally. A second mechanism for the production of protease inhibitor from angiostatin by endothelial cells is proposed to be of Michaelis-Menten type. Mathematically, this mechanism includes the former as a subcase.

Angiogenesis Inducing Agents↗
PubMed2000

Mrp4, a new mitogen-regulated protein/proliferin gene; unique in this gene family for its expression in the adult mouse tail and ear.

Mitogen-regulated proteins (also known as proliferin; mrp/plf) are nonclassical members of the PRL/GH family. They are expressed at high levels during midgestation when they are thought to induce angiogenesis and uterine growth. There are between four and six mrp/plf genes, and three different complementary DNAs have been cloned. Here we identify a fourth mrp/plf gene (mrp4) that we have cloned and characterized. MRP4 is 91% identical in amino acid sequence with the other MRP/PLF proteins but is missing two glycosylation sites that are present in the other forms. Consistent with the loss of two of three glycosylation sites, the expressed form of MRP4 has a lower apparent molecular weight compared with other MRP/PLFs. In vivo, mrp4 is expressed in the placenta and the adult skin. Expression of mrp4 messenger RNA peaks in the placenta on day 12. In the skin, mrp4 expression is specific to the ears and tails of mice. Our results suggest that, as well as having growth and angiogenic effects during pregnancy, the MRP/PLFs may have functions in nonreproductive tissues. Unique among the members of the mrp/plf family for its expression in the hair follicles of the tail and ear, MRP4 is expected to have a singular role in the growth and development of these follicles.

Amino Acid Sequence↗
PubMed1999

A unique bFGF-responsive transcriptional element.

The mitogen-regulated protein/proliferin (mrp/plf) genes encode closely related proteins that stimulate cell proliferation and angiogenesis. Basic fibroblast growth factor (bFGF) increases mrp/plf mRNA and protein production by 3T3 cells. Although the three cloned mrp/plf gene promoters are over 97% identical, only mrp3 is transcriptionally activated by bFGF. A series of truncated mrp3 promoter sequences were tested to determine the minimal promoter sequence necessary for bFGF-responsive transcription. Within the minimal bFGF-responsive mrp3 promoter fragment, a putative FGF-regulatory element (FRE) was identified. Nuclear factors that bind the FRE are present in 3T3 cells. When present upstream of a thymidine kinase basal promoter, the FRE exhibits high transcriptional activity and responds to bFGF. Thus, the FRE is a strong transcriptional element that is regulated by bFGF and that may participate in regulating the mrp3 gene and perhaps other FGF-regulated genes.

3T3 Cells↗
PubMed1999

Signaling between the placenta and the uterus involving the mitogen-regulated protein/proliferins.

The aim of this investigation was to examine signaling between the placenta and uterus during pregnancy. To do this, we determined the tissue messenger RNA and protein levels of members of a glycopeptide hormone family known to stimulate the proliferation of uterine cells and related these levels to the growth of the uterus during pregnancy in the mouse. This hormone family is known as mitogen-regulated protein (MRP); alternatively proliferin (PLF). Three mrp/plf genes, plf1, mrp3 and mrp4, are expressed by the placenta with different developmental profiles. The major increase of about 4-fold in DNA content of the uterus occurs between days 9 and 14 when MRP/PLFs are present in the placenta. By contrast, the gestational changes in estradiol-17beta levels in placental and uterine tissues and in circulation do not correlate with the period of uterine growth. The previously reported mitogenic activity of the MRP/PLFs and their gestational profiles suggest that one or more of these proteins stimulates uterine proliferation during gestation. Evidence is also presented that expression of MRP3 and/or PLF1, but not MRP4, is negatively regulated by feedback from the uterus. Our results are consistent with the hypothesis that MRP/PLFs stimulate uterine proliferation in vivo and that a uterine factor shuts off PLF1 and/or MRP3 synthesis in the latter half of gestation.

Amniotic Fluid↗
PubMed1998

Granzymes D, E, F, and G are regulated through pregnancy and by IL-2 and IL-15 in granulated metrial gland cells.

Granulated metrial gland (GMG) cells are NK cells that proliferate and differentiate within the murine uterus during pregnancy. They have been predicted to play important roles in nurturing the embryo, normal placentation, and uterine tissue remodeling. GMG cell differentiation is manifested by the accumulation of the cytolytic mediators, perforin, granzyme A, and granzyme B, within cytoplasmic granules. The signaling mechanisms required for GMG cell differentiation are largely unknown, although recent in vitro assays have implicated IL-15 in these events. In this report, we demonstrate that granzymes D, E, F, and G (granzymes D-G) are also expressed in GMG cells but at a later stage in pregnancy when compared with granzyme A expression. Whereas granzyme A is expressed in early to mid-gestation, the expression of granzymes D-G peak in mid- to late gestation. In addition, we show that the expression patterns of IL-2Rbeta and the IL-2Rgamma mRNAs overlap with that of granzyme D-G mRNAs in the pregnant uterus. Finally, we demonstrate that granzymes D-G are up-regulated by IL-2 and IL-15 in primary cultures containing GMG cells. Taken together, these results suggest that IL-2 and/or IL-15 may regulate GMG cell differentiation in vivo, and that granzymes D-G may have different functions than granzyme A during pregnancy.

Animals↗
PubMed1997

Uterocalin: a mouse acute phase protein expressed in the uterus around birth.

Mouse SIP24/24p3 is a 24 kDa lipocalin expressed in the liver and secreted into the bloodstream during the acute phase response (APR). In this report we show that SIP24/24p3 mRNA and protein are expressed in the uterus around parturition at levels higher than are found in the liver during the APR. Because of the unique expression of this lipocalin in the uterus, we have named this protein uterocalin. Contrary to its expression pattern during the APR, there is little or no expression of uterocalin in the liver during or after pregnancy. Also, unlike the APR, and despite its high level of expression in the uterus, uterocalin was not detected in the blood or amniotic fluid. Day 19 and postpartum uterine samples were examined by immunocytochemistry. Uterocalin was found in the luminal epithelium at day 19 and in the glandular epithelium in postpartum samples. Although some uterocalin remained in the luminal epithelium, most of the uterocalin was found deposited on its luminal surface. The uterus undergoes extensive tissue remodeling during pregnancy and suffers stress and tissue damage around parturition. Uterocalin could be part of the local inflammatory response associated with parturition.

Acute-Phase Proteins↗
PubMed1995

Identification of a new acute phase protein.

We have previously reported mouse SIP24 protein as a secreted inducible protein produced by quiescent Balb/c 3T3 cells. SIP24 can be produced in response to many factors, including serum, basic fibroblast growth factor, prostaglandin F2 alpha, phorbol ester, and dexamethasone. Here we present evidence to show that SIP24 is the product of mouse 24P3 mRNA. The 24P3 cDNA was originally cloned from an SV40-transformed quiescent mouse primary kidney cell culture, and it has been classified as a new member of the lipocalin protein family. We show that the SIP24/24P3 protein and mRNA increase dramatically in mouse serum and liver during the acute phase response induced by turpentine injection. Injection of mice with dexamethasone caused a modest increase of SIP24/24P3 mRNA in the liver. Tissue distribution studies revealed that SIP24/24P3 is mainly expressed in liver during the acute phase response. SIP24/24P3 was also detected in the brain and the uterus. In mouse BNL (Balb/c normal liver) cells, the production of SIP24/24P3 is stimulated by tumor necrosis factor alpha, which is a major regulator of the expression of other acute phase proteins. From its pattern of regulation, we conclude that SIP24/24P3 is a new type 1 acute phase protein.

3T3 Cells↗
PubMed1995

Cloning of the mink plasminogen activator inhibitor type-1 messenger RNA: an mRNA with a short half life.

In mink lung CCL64 epithelial cells the rate of synthesis of plasminogen activator inhibitor type I (PAI-1) increases 10-100-fold within 3 h in response to 12-O-tetradecanoyl phorbol-13-acetate (PMA). The PAI-1 gene is regulated transcriptionally. Parallel studies of the time-courses of PAI-1 synthesis and secretion and of mRNA accumulation indicate that the amount of secreted PAI-1 produced by the cells is tightly coupled to the level of its transcript. The half-life of the PAI-1 mRNA was found to be 25 min which is much shorter than previously reported for PAI-1 in other cells. Actinomycin D, which is commonly used to determine mRNA half-life, stabilized the PAI-1 mRNA. Cycloheximide also stabilized the mRNA. The short half-life and the superinducibility of PAI mRNA are properties shared with rapidly degraded mRNAs encoding protooncoproteins. A 2.97-kb cDNA clone containing the entire coding sequence of PAI-1 was isolated from a cDNA library made from mink lung CCL64 epithelial cells stimulated with PMA. The PAI-1 cDNA contains a long 3'-untranslated region (UTR) of 1720 bp whose sequence is highly conserved among PAI-1 mRNAs from different species. The PAI-1 mRNA also contains several AUUUA pentamer sequences which are the features of an A+U-rich regulatory element such as is found on the fos protooncogene mRNA. Upstream of one of these AUUUA pentamers are several highly conserved sequences that are also found in the 3' UTR of the fos and integrin receptor alpha-subunit mRNAs.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1995

Characterization of the mitogen-regulated protein (proliferin) receptor.

Mitogen-regulated protein (MRP/PLF; also called proliferin) is a member of the PRL-GH family expressed by the placenta in mid-gestation. This report describes an MRP/PLF receptor in uterine membrane preparations from pregnant mice. Peak receptor activity occurred at 11 days of gestation with a dissociation constant of 6 x 10(-10) M and maximal binding capacity of 86 fmole MRP/PLF/mg membrane protein. PRL, PL-I, and mannose-6-phosphate did not compete for binding, and GH competed weakly only at high concentrations. Primary cells cultured from uteri taken at days 8-11 of gestation responded to MRP/PLF with increases in DNA synthesis. Uterine cells from later stages of gestation did not respond to MRP/PLF. This is the first reported evidence of a function mediated by MRP/PLF and suggests a role for this protein in maternal-fetal interactions during reproduction. Thus, it seems that MRP/PLF is a placentally derived growth factor, which stimulates proliferation in the uterus in a developmentally defined period to coordinate uterine growth with fetal development.

Animals↗
PubMed1992

Opposite and independent actions of cyclic AMP and transforming growth factor beta in the regulation of type 1 plasminogen activator inhibitor expression.

We have investigated the mechanisms by which type 1 plasminogen activator inhibitor (PAI-1) is regulated by transforming growth factor beta (TGF-beta) and by epidermal growth factor (EGF) in CCL64 mink lung epithelial cells, BSC-1 monkey kidney epithelial cells, mouse embryo fibroblast (AKR-2B 84A) cells and normal rat kidney fibroblasts (NRK). TGF-beta increases PAI-1 expression in all four cell lines, and EGF acts synergistically with TGF-beta to increase PAI-1 expression in CCL64 cells but not in the other three cell lines. Here we show that PAI-1 expression can be regulated independently through two different signal transduction pathways. One pathway involves protein kinase C and is stimulated by the tumour promoter phorbol myristate acetate (PMA). Whereas preincubation with PMA completely eliminated PMA-induced PAI-1 synthesis and secretion in both CCL64 and BSC-1 cells, this treatment had no effect on TGF-beta- and EGF-induced PAI-1 levels. Therefore we conclude that protein kinase C does not mediate the effects of either EGF or TGF-beta on PAI-1 expression. The expression of PAI-1 was decreased by agents increasing intracellular cyclic AMP: (cAMP) cholera toxin, forskolin and dibutyryl cAMP lowered both the basal level and the TGF-beta- and PMA-induced levels of PAI-1 expression. These effects of cAMP-elevating agents and of TGF-beta on PAI-1 protein synthesis were also reflected in changes in TGF-beta-induced PAI-1 gene transcription, as measured by nuclear run-on. These results show that PAI-1 gene expression is sensitive to high levels of intracellular cAMP and that this effect occurs at the transcriptional level. Although increased intracellular cAMP concentrations decrease the absolute level of PAI-1 expression, the ability of TGF-beta and EGF to induce PAI-1 gene expression is unchanged. These results are discussed in relation to the observation that sensitivity to cAMP is a common feature of TGF-beta-regulated genes.

Animals↗
PubMed1992

Developing in a family way. Transforming Growth Factor Type beta and Related Proteins in Development: the Sixth Molecular, Cellular and Developmental Biology/Iowa State University Symposium, Ames, IA, USA September 20-23, 1991.

We are left with the impression that members of the TGF-beta family are critically positioned in a cascade of events regulating complex developmental processes. Roberts described the TGF-betas as providing the cells with cues to their temporal positions in a developmental program, that is, telling the cells "where they were, where they are, and where they're going." The broad diversity of cellular and tissue responses to TGF-betas and the widespread expression of their receptors suggest the TGF-betas may act as a "common currency," enabling diverse cell types to communicate with each other. Other members of the family are more restricted in their expression and the expression of their receptors, and may have a more limited and well-defined developmental role. The complex regulation of the members of the TGF-beta family is consistent with their importance as directors and coordinators of complicated physiological processes such as those occurring in the development of multicellular organisms. Their expression is highly regulated at the transcriptional and post-transcriptional levels, and their localization and activation can be affected by binding proteins and matrix proteins. We still have much to learn about the receptors for this family of growth factors, but the recent cloning of the activin and TGF-beta receptors and the discovery of their enzymatic nature has dramatically opened the way for future studies to resolve the signal transduction pathway(s) used by members of this family.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Basic fibroblast growth factor induces 3T3 fibroblasts to synthesize and secrete a cyclophilin-like protein and beta 2-microglobulin.

When stimulated by fibroblast growth factor (FGF) BALB/c 3T3 cells synthesize and secrete elevated amounts of five proteins called the 'superinducible proteins', or SIPs. The expression of these proteins is greatly enhanced if the cells are treated with cycloheximide during induction. The 24 kDa protein (SIP24) has been purified and antiserum raised against it. This protein is N-glycosylated and probably structurally constrained by one or more intramolecular disulfide bonds. The amino acid sequences of three of four peptides show significant identity with cyclophilin, an abundant cytoplasmic protein believed to mediate the immunosuppressive effects of cyclosporin A. Several members of the cyclophilin family have been identified, and cDNA clones of two cyclophilin-like proteins with signal sequences have been reported. Here we show that at least one cyclophilin-like protein is secreted and that its expression is regulated by growth factors. The 12.5 kDa protein (SIP12.5) was found to be immunoprecipitated by an antiserum raised to human beta 2-microglobulin. This protein is strongly induced by interferon, which is a characteristic of the beta 2-microglobulin gene. Thus, FGF stimulates mouse embryo 3T3 cells to produce two proteins related to immune regulatory molecules. This may reflect an interaction between immune cells and nonimmune cells that occurs in vivo during processes such as wound healing when growth factors are released locally.

3T3 Cells↗