MAP Kinase Activation Is Essential for the Development of Acute Leukemia by MLL Fusion Protein and FLT3 Tyrosine Kinase Mutation.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2067-2067
Author(s):  
Ryoichi Ono ◽  
Hidetoshi Kumgai ◽  
Hideaki Nakajima ◽  
Yukio Tonozuka ◽  
Ai Hishiya ◽  
...  
Keyword(s):  
Fusion Protein ◽  
Acute Leukemia ◽  
Tyrosine Kinase ◽  
Map Kinase ◽  
Dominant Negative ◽  
Dominant Negative Mutant ◽  
Oncogenic Potential ◽  
Kinase Activation

Abstract MLL (mixed lineage leukemia)-fusion-mediated acute leukemia in infants has frequently been found to have FLT3 overexpression or tyrosine kinase domain (TKD) mutation. We have recently developed both in vitro and in vivo leukemogenesis models where MLL fusion proteins cooperate with another FLT3 mutant, internal tandem duplication (ITD). However, little has been clear about molecular mechanism of the cooperativity between MLL fusion protein and FLT3 mutants, not only FLT3-ITD but also FLT3-TKD. The present study demonstrates that MLL-SEPT6 fusion protein associated with infantile acute leukemia cooperates in vitro with FLT3-TKD mainly through activated MAP kinase pathway, while MLL-SEPT6 cooperates with FLT3-ITD mainly through activated STAT5 pathway. We first found that the interleukin (IL) -3 dependent murine hematopoietic cell line immortalized by MLL-SEPT6, named HF6, was transformed to grow without IL-3 by forced expression of FLT3 mutants which activated MAP kinase and STAT5, as shown in IL-3 dependent murine pro-B Ba/F3 cells. A dominant negative mutant of STAT5A suppressed the proliferation of the HF6 cells transformed by FLT3-ITD more effectively than that by FLT3-TKD, similarly to the transformed Ba/F3 cells. However, unlike the transformed Ba/F3 cells, the proliferation of transformed HF6 cells was suppressed with an MEK inhibitor more effectively in the HF6 cells transformed by FLT3-TKD than by FLT3-ITD. These results suggested that, in the transformation of HF6 cells, MAP kinase activation is more critical for FLT3-TKD than STAT5, while STAT5 activation is more critical for FLT3-ITD than MAP kinase. Furthermore, HF6 cells became IL-3 independent by direct activation of Raf-MAP kinase, while Ba/F3 cells did not. In contrast, a constitutively active mutant of STAT5 enabled, not HF6, but Ba/F3 cells to grow without IL-3, thus suggesting the essential role of activation of the Raf-MAP kinase cascade in the growth of the cells expressing MLL fusion protein. We next examined the oncogenic potential of MLL-SEPT6 and either of the FLT3 mutants by leukemogenesis assays in vivo using bone marrow transplantation. Interestingly, FLT3-TKD cooperated with MLL-SEPT6 in vivo to induce acute leukemia in mice rapidly (26±5.5 days), similarly to FLT3-ITD (27±5.1 days), although the individual oncogenic potential of FLT3-TKD leading to T-cell lymphoma (119±11 days), was much weaker than that of FLT3-ITD leading to myeloproliferative disease (56±16 days). Taken together, these results suggest that MLL fusion protein can induce human acute leukemia in concert with MAP kinase activation through secondary genetic events including FLT3-TKD mutation or other mechanisms which activate MAP kinase.

scholarly journals Extracellular Signal-Regulated Kinase Binds to TFII-I and Regulates Its Activation of the c-fosPromoter

2000 ◽  
Vol 20 (4) ◽  
pp. 1140-1148 ◽  
Author(s):  
Dae-Won Kim ◽  
Brent H. Cochran
Keyword(s):  
Map Kinase ◽  
Transcriptional Activation ◽  
Dominant Negative ◽  
Binding Motif ◽  
Dependent Manner ◽  
Consensus Map ◽  
Interaction Domain ◽  
Extracellular Signal

ABSTRACT We have previously shown that TFII-I enhances transcriptional activation of the c-fos promoter through interactions with upstream elements in a signal-dependent manner. Here we demonstrate that activated Ras and RhoA synergize with TFII-I for c-fospromoter activation, whereas dominant-negative Ras and RhoA inhibit these effects of TFII-I. The Mek1 inhibitor, PD98059 abrogates the enhancement of the c-fos promoter by TFII-I, indicating that TFII-I function is dependent on an active mitogen-activated protein (MAP) kinase pathway. Analysis of the TFII-I protein sequence revealed that TFII-I contains a consensus MAP kinase interaction domain (D box). Consistent with this, we have found that TFII-I forms an in vivo complex with extracellular signal-related kinase (ERK). Point mutations within the consensus MAP kinase binding motif of TFII-I inhibit its ability to bind ERK and its ability to enhance the c-fos promoter. Therefore, the D box of TFII-I is required for its activity on the c-fos promoter. Moreover, the interaction between TFII-I and ERK can be regulated. Serum stimulation enhances complex formation between TFII-I and ERK, and dominant-negative Ras abrogates this interaction. In addition, TFII-I can be phosphorylated in vitro by ERK and mutation of consensus MAP kinase substrate sites at serines 627 and 633 impairs the phosphorylation of TFII-I by ERK and its activity on the c-fos promoter. These results suggest that ERK regulates the activity of TFII-I by direct phosphorylation.

scholarly journals Nuclear Import of IκBα Is Accomplished by a Ran-Independent Transport Pathway

2000 ◽  
Vol 20 (5) ◽  
pp. 1571-1582 ◽  
Author(s):  
Shrikesh Sachdev ◽  
Sriparna Bagchi ◽  
Donna D. Zhang ◽  
Angela C. Mings ◽  
Mark Hannink
Keyword(s):  
Nuclear Import ◽  
Nuclear Export ◽  
Dominant Negative ◽  
Dominant Negative Mutant ◽  
Nuclear Pore ◽  
Transport Pathway ◽  
Repeat Domain ◽  
Nuclear Export Receptor

ABSTRACT The inhibitor of kappa B alpha (IκBα) protein is able to shuttle between the cytoplasm and the nucleus. We have utilized a combination of in vivo and in vitro approaches to provide mechanistic insight into nucleocytoplasmic shuttling by IκBα. IκBα contains multiple functional domains that contribute to shuttling of IκBα between the cytoplasm and the nucleus. Nuclear import of IκBα is mediated by the central ankyrin repeat domain. Similar to previously described nuclear import pathways, nuclear import of IκBα is temperature and ATP dependent and is blocked by a dominant-negative mutant of importin β. However, in contrast to classical nuclear import pathways, nuclear import of IκBα is independent of soluble cytosolic factors and is not blocked by the dominant-negative RanQ69L protein. Nuclear export of IκBα is mediated by an N-terminal nuclear export sequence. Nuclear export of IκBα requires the CRM1 nuclear export receptor and is blocked by the dominant-negative RanQ69L protein. Our results are consistent with a model in which nuclear import of IκBα is mediated through direct interactions with components of the nuclear pore complex, while nuclear export of IκBα is mediated via a CRM1-dependent pathway.

Transgenic Xenopus embryos from sperm nuclear transplantations reveal FGF signaling requirements during gastrulation

Development ◽  
1996 ◽  
Vol 122 (10) ◽  
pp. 3173-3183 ◽  
Author(s):  
K.L. Kroll ◽  
E. Amaya
Keyword(s):  
Large Scale ◽  
Neural Induction ◽  
Dominant Negative ◽  
Dominant Negative Mutant ◽  
Mesoderm Induction ◽  
Fgf Signaling ◽  
Fgf Receptor ◽  
Transgenic Expression

We have developed a simple approach for large-scale transgenesis in Xenopus laevis embryos and have used this method to identify in vivo requirements for FGF signaling during gastrulation. Plasmids are introduced into decondensed sperm nuclei in vitro using restriction enzyme-mediated integration (REMI). Transplantation of these nuclei into unfertilized eggs yields hundreds of normal, diploid embryos per day which develop to advanced stages and express integrated plasmids nonmosaically. Transgenic expression of a dominant negative mutant of the FGF receptor (XFD) after the mid-blastula stage uncouples mesoderm induction, which is normal, from maintenance of mesodermal markers, which is lost during gastrulation. By contrast, embryos expressing XFD contain well-patterned nervous systems despite a putative role for FGF in neural induction.

Characterization of MAP kinase and PKC isoform and effect of ACE inhibition in hypertrophy in vivo

1999 ◽  
Vol 277 (5) ◽  
pp. H1808-H1816 ◽  
Author(s):  
L. Kim ◽  
T. Lee ◽  
J. Fu ◽  
M. E. Ritchie
Keyword(s):  
Map Kinase ◽  
Gene Activation ◽  
Pressure Overload ◽  
Ace Inhibition ◽  
Binding Activity ◽  
Sham Operation ◽  
Kinase Activation ◽  
Mitogen Activated Protein

Protein kinase C (PKC) and mitogen-activated protein (MAP) kinase activation appear important in conferring hypertrophy in vitro. However, the response of PKC and MAP kinase to stimuli known to induce hypertrophy in vivo has not been determined. We recently demonstrated that pressure-overload hypertrophy induced a transiently transfected gene driven by an hypertrophy responsive enhancer (HRE) through a marked increase in binding activity of its interacting nuclear factor (HRF). These data suggested that the HRE/HRF could serve as a target for evaluating the signal transduction events responsible for hypertrophy in vivo. Accordingly, we characterized MAP kinase and PKC isoform activation, injected HRE driven reporter gene expression, and HRF binding activity in rat hearts subjected to ascending aortic clipping or sham operation in the presence of the angiotensin-converting enzyme (ACE) inhibitor fosinopril, hydralazine, or no treatment. Analyses showed that PKC-ε and MAP kinase were acutely activated following ascending aortic ligature and that fosinopril significantly inhibited but did not completely abrogate PKC-ε and MAP kinase activation. However, fosinopril completely prevented pressure overload-mediated induction of HRE containing constructs and obviated increased HRF binding activity. These results suggest a direct relationship between ACE activity and HRE/HRF-mediated gene activation and imply that PKC-ε and MAP kinase may be involved in transducing this signal.

scholarly journals In vivo analysis of the role of aberrant histone deacetylase recruitment and RARα blockade in the pathogenesis of acute promyelocytic leukemia

2006 ◽  
Vol 203 (4) ◽  
pp. 821-828 ◽  
Author(s):  
Hiromichi Matsushita ◽  
Pier Paolo Scaglioni ◽  
Mantu Bhaumik ◽  
Eduardo M. Rego ◽  
Lu Fan Cai ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Fusion Protein ◽  
Acute Promyelocytic Leukemia ◽  
Histone Deacetylases ◽  
Retinoic Acid Receptor ◽  
Promyelocytic Leukemia ◽  
Dominant Negative

The promyelocytic leukemia–retinoic acid receptor α (PML-RARα) protein of acute promyelocytic leukemia (APL) is oncogenic in vivo. It has been hypothesized that the ability of PML-RARα to inhibit RARα function through PML-dependent aberrant recruitment of histone deacetylases (HDACs) and chromatin remodeling is the key initiating event for leukemogenesis. To elucidate the role of HDAC in this process, we have generated HDAC1–RARα fusion proteins and tested their activity and oncogenicity in vitro and in vivo in transgenic mice (TM). In parallel, we studied the in vivo leukemogenic potential of dominant negative (DN) and truncated RARα mutants, as well as that of PML-RARα mutants that are insensitive to retinoic acid. Surprisingly, although HDAC1-RARα did act as a bona fide DN RARα mutant in cellular in vitro and in cell culture, this fusion protein, as well as other DN RARα mutants, did not cause a block in myeloid differentiation in vivo in TM and were not leukemogenic. Comparative analysis of these TM and of TM/PML−/− and p53−/− compound mutants lends support to a model by which the RARα and PML blockade is necessary, but not sufficient, for leukemogenesis and the PML domain of the fusion protein provides unique functions that are required for leukemia initiation.

scholarly journals La Autoantigen Is Necessary for Optimal Function of the Poliovirus and Hepatitis C Virus Internal Ribosome Entry Site In Vivo and In Vitro

2004 ◽  
Vol 24 (15) ◽  
pp. 6861-6870 ◽  
Author(s):  
Mauro Costa-Mattioli ◽  
Yuri Svitkin ◽  
Nahum Sonenberg
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Internal Ribosome Entry Site ◽  
Ribosomal Subunit ◽  
Dominant Negative ◽  
Dominant Negative Mutant ◽  
Entry Site ◽  
Internal Ribosome Entry

ABSTRACT Translation of poliovirus and hepatitis C virus (HCV) RNAs is initiated by recruitment of 40S ribosomes to an internal ribosome entry site (IRES) in the mRNA 5′ untranslated region. Translation initiation of these RNAs is stimulated by noncanonical initiation factors called IRES trans-activating factors (ITAFs). The La autoantigen is such an ITAF, but functional evidence for the role of La in poliovirus and HCV translation in vivo is lacking. Here, by two methods using small interfering RNA and a dominant-negative mutant of La, we demonstrate that depletion of La causes a dramatic reduction in poliovirus IRES function in vivo. We also show that 40S ribosomal subunit binding to HCV and poliovirus IRESs in vitro is inhibited by a dominant-negative form of La. These results provide strong evidence for a function of the La autoantigen in IRES-dependent translation and define the step of translation which is stimulated by La.

Signaling by the Granulocyte-Colony Stimulating Factor Receptor Involves Jak2-Dependent Phosphorylation of Gab2.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2173-2173
Author(s):  
Lin Wang ◽  
Jia Xue ◽  
Seth J. Corey ◽  
Lisa J. Robinson
Keyword(s):  
Fusion Protein ◽  
Kinase Inhibitor ◽  
Dominant Negative ◽  
Site Directed Mutagenesis ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Erk Phosphorylation ◽  
Stimulating Factor

Abstract Granulocyte colony stimulating factor (G-CSF) is the major cytokine involved in neutrophil production. G-CSF has pleiotropic effects on myeloid cells, initially stimulating proliferation but later promoting differentiation. The specific signaling pathways that mediate the diverse effects of G-CSF remain incompletely understood. Recently, the scaffolding molecule Grb2-associated binder protein 2 (Gab2) was shown to play an important role in G-CSF induced myeloid differentiation (Zhu et al. Blood 2004). Ligand stimulation of the G-CSF receptor results in the rapid phosphorylation of Gab2, but the identity of the responsible kinases and the molecular events dependent on Gab2 phosphorylation remain unclear. Because Janus kinases (Jaks) play a central role in G-CSF signaling, we investigated the involvement of Jaks in G-CSF-stimulated Gab2 phosphorylation using the hematologic DT40 cell line stably transduced with the human G-CSF receptor (DT40GR). Antisense Jak1 and Jak2 constructs expressed in DT40GR cells each produced a marked reduction in their target Jak protein, but only antisense Jak2 reduced G-CSF-stimulated Gab2 phosphorylation. To determine whether Gab2 phosphorylation required Jak2 kinase activity, dominant negative Jak2 mutants lacking catalytic activity were expressed in the DT40GR cells. Expression of dominant negative Jak2 inhibited Gab2 phosphorylation in response to G-CSF. Similarly, treatment with the Jak2-selective kinase inhibitor AG490 markedly reduced G-CSF-dependent Gab2 phosphorylation. Co-immunoprecipitation studies further demonstrated a G-CSF- and Gab2 phosphorylation-dependent association of Jak2 with Gab2 in vivo, which was detectable by 30 seconds after G-CSF stimulation. To determine whether Gab2 was a direct substrate of Jak2, we performed in vitro phosphorylation studies using Gab2-GST fusion protein substrates. Jak2 immunoprecipitated from G-CSF-stimulated cells, but not from control cells, phosphorylated the Gab2 fusion protein. To identify potential Jak2 tyrosine phosphorylation sites in Gab2, we used site-directed mutagenesis to produce three Gab2 tyrosine mutants. Tyrosines 409, 452, and 476 were each replaced by phenylalanine (Y409F, Y452F, and Y476F). The Y452F and Y476F mutations of Gab2 each inhibited G-CSF-stimulated Jak2-dependent phosphorylation of Gab2, both in stably-transfected DT40GR cells and in transiently-transfected 293 cells also transduced with the G-CSF receptor. In contrast, G-CSF-stimulated Gab2 phosphorylation appeared unaffected by the Y409F mutation. We also evaluated downstream events in G-CSF signaling in cells expressing these Gab2 tyrosine- mutants. Akt and Erk phosphorylation following G-CSF stimulation was inhibited by both the Y452F and Y476F Gab2 mutations, but was unaffected by the Y409F mutation. These results suggest that Jak2 may mediate G-CSF differentiation signals through Stat-independent mechanisms.

scholarly journals MAP Kinase inhibition reshapes tumor microenvironment of mouse pancreatic cancer by depleting anti-inflammatory macrophages

2019 ◽  
Author(s):  
Pietro Delfino ◽  
Christian Neander ◽  
Dea Filippini ◽  
Sabrina L. D’Agosto ◽  
Caterina Vicentini ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Antitumor Activity ◽  
Map Kinase ◽  
Ductal Adenocarcinoma ◽  
Oncogenic Signaling ◽  
Kinase Activation ◽  
Immune Contexture ◽  
Inflammatory Macrophages

ABSTRACTThe RAF/MEK/ERK (MAP Kinase) pathway is the index oncogenic signaling towards which many compounds have been developed and tested for the treatment of KRAS-driven cancers, including pancreatic ductal adenocarcinoma (PDA). Here, we explored the immunological changes induced by targeted MEK1/2 inhibition (MEKi) using trametinib in preclinical mouse models of PDA. We evaluated the dynamic changes in the immune contexture of mouse PDA upon MEKi using a multidimensional approach (mRNA analyses, flow cytometry, and immunophenotyping). Effect of MEKi on the viability and metabolism of macrophages was investigated in vitro. We showed that transcriptional signatures of MAP Kinase activation are enriched in aggressive human PDA subtype (squamous/basal-like/quasimesenchymal), while short term MEKi treatment in mouse PDA induced subtype switching. Integrative mRNA expression and immunophenotypic analyses showed that MEKi reshapes the immune landscape of PDA by depleting rather than reprogramming macrophages, while augmenting infiltration by neutrophils. Depletion of macrophages is observed early in the course of in vivo treatment and is at least partially due to their higher sensitivity to MEKi. Tumor-associated macrophages were consistently reported to interfere with gemcitabine uptake by PDA cells. Here, our in vivo studies show a superior antitumor activity upon combination of MEKi and gemcitabine using a sequential rather than simultaneous dosing protocol. Our results show that MEK inhibition induces a dramatic remodeling of the tumor microenvironment of mouse PDA through depletion of macrophages, which substantially improves the antitumor activity of gemcitabine.

Mechanisms of Activation of the FIP1L1-PDGFRα Fusion Kinase.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2422-2422
Author(s):  
Elizabeth H. Stover ◽  
Jan Cools ◽  
D. Gary Gilliland
Keyword(s):  
Fusion Protein ◽  
Tyrosine Kinase ◽  
Kinase Inhibitor ◽  
Hypereosinophilic Syndrome ◽  
Fusion Partner ◽  
Myeloproliferative Disease ◽  
Alternative Mode ◽  
Type Iii

Abstract We recently identified the FIP1L1-PDGFRα fusion protein as a frequent cause of hypereosinophilic syndrome (HES), a disorder characterized by persistent eosinophilia and organ dysfunction. ~60% of HES patients who are sensitive to imatinib, a selective tyrosine kinase inhibitor, harbor the FIP1L1-PDGFRα fusion. The fusion is expressed as a consequence of an interstitial chromosomal deletion of human chromosome 4 that fuses a novel protein FIP1L1 to the cytoplasmic domain of the tyrosine kinase PDGFRα, a type III receptor tyrosine kinase (RTK). The fusion protein is a constitutively active kinase and has transforming properties in vitro and in vivo that are inhibited by imatinib. In order to understand the mechanism of activation of the FIP1L1-PDGFRα fusion kinase, a series of deletions of FIP1L1 were fused to PDGFRα and the fusions were tested for transforming activity. The data suggested that the FIP1L1 moiety was in fact dispensable for PDGFRα activation. For example, substitution of FIP1L1 with the Myc-epitope fused to PDGFRA still resulted in PDGFRα autophosphorylation; transformation of Ba/F3 cells to IL-3 independent growth; and induction of a myeloproliferative disease in a murine bone marrow transplant assay. Structural analyses of other type III RTKs, such as FLT3, have identified an autoinhibitory function of the juxtamembrane (JM) domain. Thus, the lack of requirement for FIP1L1 suggests that activation of the FIP1L1-PDGFRa fusion kinase might be caused by disruption of an autoinhibitory JM domain in PDGFRα. Indeed, in patients with the FIP1L1-PDGFRα fusion, the breakpoints in PDGFRA are tightly clustered within exon 12, which encompasses the JM domain. Whereas activation of most known fusion kinases relies on enforced dimerization by a fusion partner, disruption of an autoinhibitory JM domain may be an alternative mode of fusion kinase activation.

p85α Regulatory Subunit of Class IA PI-3Kinase Regulates Osteoclast Function(s) and Bone Mass.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2223-2223
Author(s):  
Veerendra Munugalavadla ◽  
Emily Sims ◽  
David A. Ingram ◽  
Alexander Robling ◽  
Reuben Kapur
Keyword(s):  
Bone Mass ◽  
Map Kinase ◽  
Intracellular Signaling ◽  
New Drugs ◽  
Regulatory Subunit ◽  
Regulatory Subunits ◽  
Kinase Activation ◽  
Osteoclast Function

Abstract Osteoclasts (OCs) play an indispensable role in regulating bone remodeling. In adults, a significant number of skeletal diseases have been linked to abnormal osteoclast function(s), including rheumatoid arthritis, periodontal disease, multiple myeloma, and metastatic cancers. Although, a clear picture of the critical players that regulate osteoclastogenesis and bone resorption has begun to emerge; further studies detailing the intracellular signaling pathways is necessary for the rationale development of new drugs for the treatment of bone disorders involving OCs. While recent studies utilizing pharmacologic inhibitors of PI-3Kinase have suggested a role for this pathway in osteoclastogenesis, these inhibitors interfere with the function of all classes of PI-3Kinase and result in extensive in vivo toxicity. Therefore, to therapeutically manipulate PI-3Kinase signaling cascade in osteoclasts, additional data evaluating the specific role of individual PI-3Kinase isoforms is necessary. Class IA PI-3Kinase are heterodimeric kinases consisting of a regulatory subunit and a catalytic subunit. Five different proteins, namely p85α, p55α, p50α, p85β, and p55γ, have been identified to date as the regulatory subunits. The p85α, p55α, and p50α proteins are derived from the same gene locus by alternative splicing mechanism. In contrast, distinct genes encode the p85β and p55γ subunits. Utilizing mice deficient in the expression of p85α subunit, we have recently shown that p85α subunit of PI-3Kinase plays an important role in regulating growth and actin based functions in bone marrow (BM) derived macrophages. Here, we demonstrate that OCs express multiple regulatory subunits of class IA PI-3Kinase, including p85α, p85β, p50α and p55α. Deficiency of p85α in OCs alone results in a significant increase in bone mass and bone density (% bone volume [BV]/trabecular volume [TV]: WT 6.7±0.01 vs p85α−/− 14±0.01*, *p<0.01). Histologic sections of p85α −/− bones reveal markedly increased cortical and trabecular mass. Despite their increased bone mass, mutant mice contain significantly greater numbers of OCs in vivo compared to wildtype controls (WT 45.6 vs p85α −/− 118*, *p<0.01). Thus, although OCs appear in p85α −/− mice, nonetheless, the bones of these mice become osteosclerotic, suggesting that osteoclasts lacking p85α may be defective. Consistent with this notion, p85α −/− BM derived OCs show reduced growth and differentiation in response to M-CSF and RANKL stimulation in vitro. Impaired differentiation due to p85α deficiency is manifested in the form of a significant reduction in TRAP positive multinucleated OCs (WT: 23.6±4 vs p85α −/−: 11.7±5*, n=3, *p<0.01), which is associated with a significant reduction in the activation of Akt and ERK MAP kinase. The transcription factor microphthalmia (MITF) is required for multinucleation of OCs. Mutations in MITF result in severe osteopetrosis. Recent studies have suggested that M-CSF induced ERK MAP kinase activation regulates MITFs function during multinucleation, therefore, we examined the expression of MITF in p85α −/− OCs. A 80% reduction in the expression of MITF was observed in p85α −/− OCs compared to controls. Remarkably, the defects in p85α deficient OCs were observed in spite of the continuous expression of p85β, p50α and p55α subunits, suggesting that p85α functions with specificity in regulating OC functions in vivo, in part by modulating the expression of MITF. Thus, p85α is a potential new target for antiosteoporosis therapy.

Sign in / Sign up

Export Citation Format

Share Document