Evidence of a role for a non‐matrix‐type metalloproteinase activity in the shedding of syndecan‐1 from human myeloma cells

Holen, Ingunn; Drury, Noel L.; Hargreaves, Philip G.

doi:10.1046/j.1365-2141.2001.02963.x

Cited by 32 publications

(24 citation statements)

References 37 publications

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“…In particular, ERK1/2 and PKC signaling have been shown to be required for RANTES-induced shedding of syndecan-1 and syndecan-4 in HeLa cells (5) and for EGF-and thrombin receptor-induced shedding in mouse epithelial cells (8). Most other reports on the mechanism of syndecan shedding have focused on the involvement of intracellular protein tyrosine kinase (29) and matrix metalloproteinase (MMP) (1,11,21) activity in this process.…”

Section: Discussionmentioning

confidence: 99%

Mechanical strain regulates syndecan-4 expression and shedding in smooth muscle cells through differential activation of MAP kinase signaling pathways

Julien¹,

Wang²,

Haller³

et al. 2007

American Journal of Physiology-Cell Physiology

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Julien MA, Wang P, Haller CA, Wen J, Chaikof EL. Mechanical strain regulates syndecan-4 expression and shedding in smooth muscle cells through differential activation of MAP kinase signaling pathways. Am J Physiol Cell Physiol 292: C517-C525, 2007. First published July 5, 2006; doi:10.1152 doi:10. /ajpcell.00093.2006 belongs to a family of transmembrane proteoglycans, acts as a coreceptor for growth factor binding as well as cell-matrix and cell-cell interactions, and is induced in neointimal smooth muscle cells (SMCs) after balloon catheter injury. We investigated S4 expression in SMCs in response to several force profiles and the role of MAP kinase signaling pathways in regulating these responses. S4 mRNA expression increased in response to 5% and 10% cyclic strain (4 h: 200 Ϯ 34% and 182 Ϯ 17%, respectively; P Ͻ 0.05) before returning to basal levels by 24 h. Notably, the SMC mechanosensor mechanism was reset after an initial 24-h "preconditioning" period, as evident by an increase in S4 gene expression following a change in cyclic stress from 10% to 20% (28 h: 181 Ϯ 1%; P Ͻ 0.05). Mechanical stress induced a late decrease in cell-associated S4 protein levels (24 h: 70 Ϯ 6%; P Ͻ 0.05), with an associated increase in S4 shedding (24 h: 537 Ϯ 109%; P Ͻ 0.05). To examine the role of MAP kinases, cells were treated with U-0126 (ERK1/2 inhibitor), SB-203580 (p38 inhibitor), or JNKI I (JNK/SAPK inhibitor). Late reduction in cell-associated S4 levels was attributed to ERK1/2 and p38 signaling. In contrast, accelerated S4 shedding required both ERK1/2 (5-fold reduction in accelerated shedding; P Ͻ 0.05) and JNK/SAPK (4-fold reduction; P Ͻ 0.05) signaling. Given the varied functions of S4, stress-induced effects on SMC S4 expression and shedding may represent an additional component of the proinflammatory, growthstimulating pathways that are activated in response to changes in the mechanical microenvironment of the vascular wall.

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Section: Discussionmentioning

confidence: 99%

Mechanical strain regulates syndecan-4 expression and shedding in smooth muscle cells through differential activation of MAP kinase signaling pathways

Julien¹,

Wang²,

Haller³

et al. 2007

American Journal of Physiology-Cell Physiology

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“…20 Others have demonstrated that syndecan-1-transfected ARH-77 B-lymphoid cells are less invasive than the wild-type cells, which have no endogenous syndecan-1. 33 Syndecan-1 is also constitutively shed from the cell surface, 34,35 and ARH-77 cells engineered to produce a soluble form of this transmembrane heparan sulfate proteoglycan are hyperinvasive. 36 The proliferation of the 5T2MM cells increased during the disease progression, parallel with their differentiation into CD45 Ϫ cells.…”

Section: Discussionmentioning

confidence: 99%

Multiple myeloma tumor progression in the 5T2MM murine model is a multistage and dynamic process of differentiation, proliferation, invasion, and apoptosis

Asosingh

Raeve

Riet

et al. 2003

Blood

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IntroductionMultiple myeloma (MM) is still an incurable plasma cell cancer, predominantly localized in the bone marrow (BM). Our group demonstrated that the in vivo homing of these malignant cells to the BM is a selective process of directed migration and selective survival in this organ. 1 Once the cells have entered the BM, they have an intensive cross-talk with the BM stromal cells and induce a microenvironment that supports their survival and growth. 2 At time of diagnosis, MM is already a well-established disease. So far myeloma research has been focused on homing and other mechanisms involved in the clinical stage of the disease. The processes involved in the earlier, preclinical, stages are unknown. In this work we took a first step in illumination of the preclinical stages. Since such investigation requires an in vivo model, the 5T2MM experimental mouse model was used. Animals intravenously inoculated with MM cells were analyzed during the entire process of myeloma progression and monitored for 3 markers: CD45, CD138 (syndecan-1), and interleukin 6 receptor (IL-6R). CD45 is a transmembrane protein tyrosine phosphatase, expressed on all B-cells. During maturation toward plasma cells the CD45 expression is gradually down-regulated. Fully matured plasma cells are CD45 Ϫ . 3 In myeloma patients both CD45 ϩ and CD45 Ϫ MM cells have been observed. [4][5][6] More recently, CD45 appeared to be a predictor of therapeutic response. 7 Myeloma patients were grouped according to percentages of CD45 bright , CD45 low , and CD45 Ϫ MM cells, and grouping was associated with clinical outcome: patients with a high percentage of CD45 Ϫ MM cells had the poorest outcome. The significance of this CD45 heterogeneity, from a biologic point of view, is, however, not understood. In the present work CD45 was used as a differentiation marker together with CD138. CD138 is a transmembrane heparan sulfate proteoglycan expressed on sessile B cells. All pre-B cells are CD138 ϩ , but during circulation in the peripheral blood CD138 expression is lost and CD138 is re-expressed on mature plasma cells in the BM. Immature CD45 ϩ MM cells are CD138 Ϫ . CD138 is also proteolytically cleaved and shed from the cell surface, and CD138 Ϫ MM cells appeared to possess a higher invasive capacity. 8 IL-6R consists of 2 subunits: an ␣ chain (gp80, CD126), which specifically binds IL-6, and a shared ␤ chain (gp130, CD130), which is responsible for the signal transduction. 9-11 IL-6 is a growth factor for MM cells, 12,13 and, worthy of mention in this work, it is required in the early stages of plasma cells in the BM to escape apoptosis. 14 We report herein a multistage process of myeloma disease progression based on the evolution of serum M component (paraprotein) and tumor load. Flow-cytometric analysis demonstrated a CD45 ϩ CD138 Ϫ IL-6R␣ ϩ phenotype of the majority of MM cells in the initial stage of tumor progression. Toward the end Materials and methods 5T2MM myeloma model5T2MM myeloma cells originate from spontaneously developed myeloma in elder...

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“…5 Total PKC activity has been reported to be elevated in carcinomas of breast 6 and lung. 7 In MM, PKC has been implicated in the shedding of CD138 8 and the IL-6 receptor, 9 both of which are thought to play important roles in tumor progression. Eleven isoforms of PKC have been identified, and these have been separated into 3 subgroups: (1) the conventional calcium-dependent and DAG (diacylglycerol)-dependent PKCs (cPKCs: ␣, ␤ I , ␤ II , ␥), (2) the nonconventional calcium-independent but DAG-dependent PKCs (nPKCs: ␦, ε, , , ), and (3) the atypical calcium-independent and DAGunresponsive PKCs (aPKCs: , ).…”

Section: Introductionmentioning

confidence: 99%

PKC412 demonstrates JNK-dependent activity against human multiple myeloma cells

Sharkey

Khong

Spencer

2006

Blood

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The effect and mode of action of the protein kinase C (PKC) inhibitor PKC412 on human multiple myeloma (MM) cell lines (HMCLs) and primary MM cells was explored. We found that PKC412 induced apoptosis of HMCLs and primary MM cells with variable efficacy; however, some activity was seen against all HMCLs and primary MM cells with at least 0.5 M PKC412. PARP cleavage and decreased PKC activity was observed in all HMCLs tested. Furthermore, PKC412 inhibited C-FOS transcription and nuclear protein expression, induced reactive oxygen species (ROS) production, and induced both sustained C-JUN expression and phosphorylation. The latter was inhibited by cotreatment with the JNK inhibitor SP600125, which similarly abrogated PKC412-induced apoptosis, suggesting that PKC412-induced apoptosis is a JNKdependent event. PKC412 treatment secondarily induced prosurvival stress responses as evidenced by activation of NFB and increased expression of the heat shock proteins HSP70 and HSP90. IntroductionMultiple myeloma (MM) is a B-cell malignancy, which occurs predominantly at an older age and is still incurable despite progress in treatment. 1 The investigation of novel anticancer drugs for the treatment of this disease is therefore warranted. Protein kinase C (PKC) is a phospholipid-dependent, serine/threonine kinase responsible for signal transduction in response to growth factors, hormones, and neurotransmitters. 2 PKC plays an important role in cell-growth regulation and tumor promotion 3 and has also been implicated in metastasis 4 and chemotherapy-associated multidrug resistance. 5 Total PKC activity has been reported to be elevated in carcinomas of breast 6 and lung. 7 In MM, PKC has been implicated in the shedding of CD138 8 and the IL-6 receptor, 9 both of which are thought to play important roles in tumor progression. Eleven isoforms of PKC have been identified, and these have been separated into 3 subgroups: (1) the conventional calcium-dependent and DAG (diacylglycerol)-dependent PKCs (cPKCs: ␣, ␤ I , ␤ II , ␥), (2) the nonconventional calcium-independent but DAG-dependent PKCs (nPKCs: ␦, ε, , , ), and (3) the atypical calcium-independent and DAGunresponsive PKCs (aPKCs: , ).The PKC inhibitor PKC412 (N-benzylstaurosporine) is a derivative of the naturally occurring alkaloid staurosporine and has been shown to inhibit the conventional isoforms of PKC (␣, ␤ I , ␤ II , ␥). PKC412 has been shown to have an antitumor effect on human non-small-cell lung cancer cells 10 and myeloma cells 11,12 and has also been shown to inhibit growth factor-dependent C-FOS mRNA expression. 13 PKC412 has also shown antitumor activity in a murine model of myeloproliferative disease 14 as well as in an FGFR3 TDII-induced murine model of B-cell lymphoma. 11The AP-1 transcription factor consists of homodimers of Jun proteins or heterodimers of Fos and Jun proteins 15,16 and plays a key role in the regulation of expression of genes involved in DNA repair, cell proliferation, cell-cycle arrest, death by apoptosis, and tissue and extracellular matr...

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Evidence of a role for a non‐matrix‐type metalloproteinase activity in the shedding of syndecan‐1 from human myeloma cells

Cited by 32 publications

References 37 publications

Mechanical strain regulates syndecan-4 expression and shedding in smooth muscle cells through differential activation of MAP kinase signaling pathways

Mechanical strain regulates syndecan-4 expression and shedding in smooth muscle cells through differential activation of MAP kinase signaling pathways

Multiple myeloma tumor progression in the 5T2MM murine model is a multistage and dynamic process of differentiation, proliferation, invasion, and apoptosis

PKC412 demonstrates JNK-dependent activity against human multiple myeloma cells

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