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Biomedical subjects

Michael Karin

Publications and source records attributed to Michael Karin.

At least 91 records · Page 5Linked to original sources
PubMed2003

NF-kappaB in cancer: a marked target.

The imbalance between proliferation and programmed cell death (apoptosis) is one of the critical cellular events that lead to oncogenesis. While there is no doubt that uncontrolled cell proliferation is essential for the development of cancer, deregulation of apoptosis may play an equally important role in this process. Inhibition of apoptosis prevents the death of tumor cells with DNA damage either associated with carcinogenic initiation or cancer therapy. The transcription factor NF-kappaB is a key regulator in oncogenesis. By promoting proliferation and inhibiting apoptosis, NF-kappaB tips the balance between proliferation and apoptosis toward malignant growth in tumor cells.

Animals↗
PubMed2003

IKKbeta is required for prevention of apoptosis mediated by cell-bound but not by circulating TNFalpha.

IkappaB kinase beta (IKKbeta) is required for NF-kappaB activation and suppression of TNFalpha-mediated liver apoptosis. To investigate how IKKbeta suppresses apoptosis, we generated hepatocyte-specific Ikkbeta knockout mice, Ikkbeta(Deltahep), which exhibit little residual NF- kappaB activity but are healthy with normal liver function. Unexpectedly, Ikkbeta(Deltahep) mice are slightly more sensitive than controls to LPS-induced liver apoptosis but are highly susceptible to liver destruction following concanavalin A (ConA)-induced T cell activation. Unlike LPS, a potent inducer of circulating TNFalpha, ConA exerts cytotoxic effects through cell-bound TNFalpha, which activates type 1 and 2 TNF receptors (TNFR). While TNFR2 does not contribute to NF-kappaB activation, it is important for ConA-induced JNK activation, which is augmented by the absence of IKKbeta. Using JNK-deficient mice we show that JNK is required for ConA-induced liver damage. Thus, the antiapoptotic function of IKKbeta, which is most critical in situations that involve cell-bound TNFalpha, is mediated partially through attenuation of JNK activity.

Animals↗
PubMed2003

CK2 Is a C-Terminal IkappaB Kinase Responsible for NF-kappaB Activation during the UV Response.

NF-kappaB is activated in response to proinflammatory stimuli, infections, and physical stress. While activation of NF-kappaB by many stimuli depends on the IkappaB kinase (IKK) complex, which phosphorylates IkappaBs at N-terminal sites, the mechanism of NF-kappaB activation by ultraviolet (UV) radiation remained enigmatic, as it is IKK independent. We now show that UV-induced NF-kappaB activation depends on phosphorylation of IkappaBalpha at a cluster of C-terminal sites that are recognized by CK2 (formerly casein kinase II). Furthermore, CK2 activity toward IkappaB is UV inducible through a mechanism that depends on activation of p38 MAP kinase. Inhibition of this pathway prevents UV-induced IkappaBalpha degradation and increases UV-induced cell death. Thus, the p38-CK2-NF-kappaB axis is an important component of the mammalian UV response.

Binding Sites↗
PubMed2003

JNK1 is required for maintenance of neuronal microtubules and controls phosphorylation of microtubule-associated proteins.

Microtubules (MTs) play an important role in elaboration and maintenance of axonal and dendritic processes. MT dynamics are modulated by MT-associated proteins (MAPs), whose activities are regulated by protein phosphorylation. We found that a member of the c-Jun NH(2)-terminal protein kinase (JNK) subgroup of MAP kinases, JNK1, is involved in regulation of MT dynamics in neuronal cells. Jnk1(-/-) mice exhibit disrupted anterior commissure tract formation and a progressive loss of MTs within axons and dendrites. MAP2 and MAP1B polypeptides are hypophosphorylated in Jnk1(-/-) brains, resulting in compromised ability to bind MTs and promote their assembly. These results suggest that JNK1 is required for maintaining the cytoskeletal integrity of neuronal cells and is a critical regulator of MAP activity and MT assembly.

Animals↗
PubMed2003

NF-kappaB in mammary gland development and breast cancer.

Nuclear factor of kappaB (NF-kappaB) is a group of sequence-specific transcription factors that is best known as a key regulator of the inflammatory and innate immune responses. Recent studies of genetically engineered mice have clearly indicated that NF-kappaB is also required for proper organogenesis of several epithelial tissues, including the mammary gland. Mice have shown severe lactation deficiency when NF-kappaB activation is specifically blocked in the mammary gland. In addition, there are strong suggestions that NF-kappaB may play an important role in the etiology of breast cancer. Elevated NF-kappaB DNA-binding activity is detected in both mammary carcinoma cell lines and primary human breast cancer tissues.

Animals↗
PubMed2003

Identification of NAP1, a regulatory subunit of IkappaB kinase-related kinases that potentiates NF-kappaB signaling.

The IkappaB kinase (IKK)-related kinase NAK (also known as TBK or T2K) contributes to the activation of NF-kappaB-dependent gene expression. Here we identify NAP1 (for NAK-associated protein 1), a protein that interacts with NAK and its relative IKK epsilon (also known as IKKi). NAP1 activates NAK and facilitates its oligomerization. Interestingly, the NAK-NAP1 complex itself effectively phosphorylated serine 536 of the p65/RelA subunit of NF-kappaB, and this activity was stimulated by tumor necrosis factor alpha (TNF-alpha). Overexpression of NAP1 specifically enhanced cytokine induction of an NF-kappaB-dependent, but not an AP-1-dependent, reporter. Depletion of NAP1 reduced NF-kappaB-dependent reporter gene expression and sensitized cells to TNF-alpha-induced apoptosis. These results define NAP1 as an activator of IKK-related kinases and suggest that the NAK-NAP1 complex may protect cells from TNF-alpha-induced apoptosis by promoting NF-kappaB activation.

Adaptor Proteins, Signal Transducing↗
PubMed2003

Inhibition of IkappaB kinase by a new class of retinoid-related anticancer agents that induce apoptosis.

The transcription factor NF-kappaB is overexpressed or constitutively activated in many cancer cells, where it induces expression of antiapoptotic genes correlating with resistance to anticancer therapies. Small molecules that inhibit the NF-kappaB signaling pathway could therefore be used to induce apoptosis in NF-kappaB-overexpressing tumors and potentially serve as anticancer agents. We found that retinoid antagonist MX781 inhibited the activation of NF-kappaB-dependent transcriptional activity in different tumor cell lines. MX781 was able to completely inhibit tumor necrosis factor alpha-mediated activation of IkappaB kinase (IKK), the upstream regulator of NF-kappaB. Inhibition of IKK activity resulted from direct binding of MX781 to the kinase, as demonstrated by in vitro inhibition studies. Two other molecules, MX3350-1 and CD2325, which are retinoic acid receptor gamma-selective agonists, were capable of inhibiting IKK in vitro, although they exerted variable inhibition of IKK and NF-kappaB activities in intact cells in a cell type-specific manner. However, N-(4-hydroxyphenyl)-retinamide, another apoptosis-inducing retinoid, and retinoic acid as well as other nonapoptotic retinoids did not inhibit IKK. Inhibition of IKK by the retinoid-related compounds and other small molecules correlated with reduced cell proliferation and increased apoptosis. Reduced cell viability was also observed after overexpression of an IKKbeta kinase-dead mutant or the IkappaBalpha superrepressor. The induction of apoptosis by the retinoid-related molecules that inhibited IKK was dependent on caspase activity but independent of the retinoid receptors. Thus, the presence of an excess of retinoic acid or a retinoid antagonist did not prevent the inhibition of IKK activation by MX781 and CD2325, indicating a retinoid receptor-independent mechanism of action.

Antineoplastic Agents↗
PubMed2003

Proteotyping of mammary tissue from transgenic and gene knockout mice with immunohistochemical markers: a tool to define developmental lesions.

Through the use of transgenic and gene knockout mice, several studies have identified specific genes required for the functional development of mammary epithelium. Although histological and milk protein gene analyses can provide useful information regarding functional differentiation, they are limited in their ability to precisely define the molecular lesions. For example, mice that carry a mutation in one of the subunits of the IkappaB kinase, IKKalpha, cannot lactate despite the presence of histologically normal alveolar compartment and the expression of milk protein genes. To further define and understand such lesions on a molecular level, we sought evidence for proteins that are differentially expressed during mammary gland development with a view to generating a tissue proteotype. Using database screens and immunohistochemical analyses, we have identified three proteins that exhibit distinct profiles. Here, using mouse models as test biological systems, we demonstrate the development and application of mammary tissue proteotyping and its use in the elucidation of specific developmental lesions. We propose that the technique of proteotyping will have wide applications in the analyses of defects in other mouse models.

Animals↗
PubMed2002

The control of mRNA stability in response to extracellular stimuli.

Regulated mRNA turnover is a highly important process in control of gene expression. The specific sequence elements in mRNA modulate the stability of different mRNAs, which varies considerably in response to extracellular stimuli. But the mechanistic basis for regulation of mRNA turnover remains nebulous. Recent works indicate that several signaling pathways have been implicated in regulating the decay of specific mRNA and certain ARE binding proteins mediate rapid degradation of the mRNAs. This review provides a current knowledge of diverse extracellular signals contributing to stabilization of short-lived mRNA.

Animals↗
PubMed2002

A central role for JNK in obesity and insulin resistance.

Obesity is closely associated with insulin resistance and establishes the leading risk factor for type 2 diabetes mellitus, yet the molecular mechanisms of this association are poorly understood. The c-Jun amino-terminal kinases (JNKs) can interfere with insulin action in cultured cells and are activated by inflammatory cytokines and free fatty acids, molecules that have been implicated in the development of type 2 diabetes. Here we show that JNK activity is abnormally elevated in obesity. Furthermore, an absence of JNK1 results in decreased adiposity, significantly improved insulin sensitivity and enhanced insulin receptor signalling capacity in two different models of mouse obesity. Thus, JNK is a crucial mediator of obesity and insulin resistance and a potential target for therapeutics.

Adipose Tissue↗
PubMed2002

Macrophage apoptosis by anthrax lethal factor through p38 MAP kinase inhibition.

The bacterium Bacillus anthracis causes the death of macrophages, which may allow it to avoid detection by the innate immune system. We found that B. anthracis lethal factor (LF) selectively induces apoptosis of activated macrophages by cleaving the amino-terminal extension of mitogen-activated protein kinase (MAPK) kinases (MKKs) that activate p38 MAPKs. Because macrophages that are deficient in transcription factor nuclear factor kappaB (NF-kappaB) are also sensitive to activation-induced death and p38 is required for expression of certain NF-kappaB target genes, p38 is probably essential for synergistic induction of those NF-kappaB target genes that prevent apoptosis of activated macrophages. This dismantling of the p38 MAPK module represents a strategy used by B. anthracis to paralyze host innate immunity.

Animals↗
PubMed2002

Essential role of p38 mitogen-activated protein kinase in contact hypersensitivity.

The present study was designed to elucidate the role of p38 mitogen-activated protein kinase (p38) in the pathogenesis of inflammation, using a mouse contact hypersensitivity (CHS) model induced by 2,4-dinitro-1-fluorobenzene (DNFB). Ear swelling was induced by challenge with DNFB, accompanied by infiltration of mononuclear cells, neutrophils, and eosinophils and a marked increase in mRNA levels of cytokines such as interleukin (IL)-2, interferon (IFN)-gamma, IL-4, IL-5, IL-1beta, IL-18, and tumor necrosis factor-alpha in the challenged ear skin. Both ear swelling and the number of infiltrated cells in DNFB-challenged ear skin were significantly inhibited by treatment with SB202190, a p38 inhibitor. Furthermore, the DNFB-induced expression of all cytokines except IL-4 was significantly inhibited by treatment with SB202190. Ribonuclease protection assay revealed that the mRNA levels of chemokines such as IP-10 and MCP-1 in ear skin were markedly increased at 24 h after challenge with DNFB. The induction of these chemokines was significantly inhibited by treatment with SB202190. In p38alpha +/- mice, both ear swelling and infiltration of cells induced by DNFB were reduced compared with those in wild-type mice. However, induction of cytokines by DNFB was also observed in p38alpha +/- mice, although the induction of IFN-gamma, IL-5, and IL-18 was typically reduced compared with that in wild-type mice. Challenge with DNFB slightly induced IP-10 and MCP-1 mRNA in p38alpha +/- mice, with weaker signals than those in SB202190-treated wild-type mice. These results suggest that p38 plays a key role in CHS and is an important target for the treatment of CHS.

Allergens↗
PubMed2002

Joint damage and inflammation in c-Jun N-terminal kinase 2 knockout mice with passive murine collagen-induced arthritis.

OBJECTIVE: Previous studies have demonstrated that inhibition of c-Jun N-terminal kinase (JNK) decreases joint destruction in the rat adjuvant arthritis model. The present study was undertaken to investigate whether selective loss of JNK-2 function decreases joint destruction in JNK-2 knockout mice, in order to determine the role of this isoform in inflammatory arthritis. METHODS: Passive collagen-induced arthritis (CIA) was induced in Jnk2(-/-) and wild-type mice by administering anti-type II collagen antibodies. Arthritis was assessed daily using a semiquantitative clinical scoring system. Fibroblast-like synoviocytes (FLS) were prepared from Jnk2(-/-) and wild-type mice, and JNK protein expression was determined by Western blot analysis. Matrix metalloproteinase 13 (MMP-13) expression was determined by Northern blot analysis, and activator protein 1 (AP-1) binding activity by electromobility shift assay (EMSA). RESULTS: The JNK protein level in Jnk2(-/-) mice with CIA was 22% of that in wild-type mice with CIA (P < 0.001), and mainly the 46-kd isoform was expressed in the former group. Surprisingly, clinical arthritis was slightly more severe in the Jnk2(-/-) mice. Histologic scores for synovial inflammation were not significantly different. However, Safranin O-stained sections from the Jnk2(-/-) mice exhibited significantly less joint damage. Although joint destruction was decreased in Jnk2(-/-) mice with CIA, EMSA and Northern blot analysis of total joint extracts revealed similar levels of AP-1 binding and MMP-13 expression in Jnk2(-/-) and wild-type mice. The lack of correlation with AP-1 activity and MMP expression was probably because non-FLS cells in the joint may express more JNK-1 than do FLS. CONCLUSION: JNK-2 is a determinant of matrix degradation, but it has little effect on inflammation in arthritis. Complete inhibition of MMP expression and joint destruction will likely require combined JNK-1 and JNK-2 inhibition.

Animals↗
PubMed2002

Missing pieces in the NF-kappaB puzzle.

The regulation of the transcription factor NF-kappaB activity occurs at several levels including controlled cytoplasmic-nuclear shuttling and modulation of its transcriptional activity. A critical component in NF-kappaB regulation is the IkappaB kinase (IKK) complex. This review is focused on recent progress as well as unanswered questions regarding the regulation and function of NF-kappaB and IKK.

Active Transport, Cell Nucleus↗
PubMed2002

The lymphotoxin-beta receptor induces different patterns of gene expression via two NF-kappaB pathways.

The lymphotoxin-beta receptor (LTbetaR) plays critical roles in inflammation and lymphoid organogenesis through activation of NF-kappaB. In addition to activation of the classical NF-kappaB, ligation of this receptor induces the processing of the cytosolic NF-kappaB2/p100 precursor to yield the mature p52 subunit, followed by translocation of p52 to the nucleus. This activation of NF-kappaB2 requires NIK and IKKalpha, while NEMO/IKKgamma is dispensable for p100 processing. IKKbeta-dependent activation of canonical NF-kappaB is required for the expression but not processing of p100 and for the expression of proinflammatory molecules including VCAM-1, MIP-1beta, and MIP-2 in response to LTbetaR ligation. In contrast, IKKalpha controls the induction by LTbetaR ligation of chemokines and cytokines involved in lymphoid organogenesis, including SLC, BLC, ELC, SDF1, and BAFF.

Active Transport, Cell Nucleus↗
PubMed2002

Nuclear export of NF90 is required for interleukin-2 mRNA stabilization.

In response to T cell activation signals, the half-life of interleukin-2 (IL-2) mRNA is greatly extended. The cis elements mediating IL-2 mRNA stabilization are located in its 5' and 3' untranslated regions (UTR). The 3'UTR also contains AU-rich elements (AREs) that mediate rapid IL-2 mRNA degradation in the cytoplasm of nonstimulated T cells. NF90, a previously described RNA binding protein, binds to a subregion of the 3'UTR that contains several AREs and slows down the degradation of IL-2 mRNA. In nonstimulated cells, NF90 is mostly nuclear, but T cell activation results in its accumulation in the cytoplasm. The nuclear export of NF90 is required for IL-2 mRNA stabilization.

3' Untranslated Regions↗
PubMed2002

Redundant pathways for negative feedback regulation of bile acid production.

The orphan nuclear hormone receptor SHP has been proposed to have a key role in the negative feedback regulation of bile acid production. Consistent with this, mice lacking the SHP gene exhibit mild defects in bile acid homeostasis and fail to repress cholesterol 7-alpha-hydroxylase expression in response to a specific agonist for the bile acid receptor FXR. However, this repression is retained in SHP null mice fed bile acids, demonstrating the existence of compensatory repression pathways of bile acid signaling. We provide evidence for two such pathways, based on activation of the xenobiotic receptor PXR or the c-Jun N-terminal kinase JNK. We conclude that redundant mechanisms regulate this critical aspect of cholesterol homeostasis.

Animals↗