ライフサイエンスコーパス: p38delta

1 p38delta can be activated by MKK3 and MKK6, known activa

2 p38delta counteracts the activity of its downstream targ

3 p38delta is highly expressed in salivary gland, pituitar

4 p38delta phosphorylates ATF-2 and PHAS-I, but not MAPK-a

5 t on enzyme activity of p38beta, p38beta(2), p38delta, or on c-Jun N-terminal kinase, another stress-

6 n kinase C isoforms, Ras, MEKK1, MEK3, and a p38delta-extracellular signal regulated kinase 1/2 compl

7 rding this inverse regulation, we describe a p38delta-ERK1/2 complex that may coordinate these change

8 Thus, aberrant p38delta-PKD1 signaling in neutrophils may underlie deve

9 se 3 (MLK3) and IB2 synergistically activate p38delta but not the MAPKs JNK-1 and p38alpha.

10 accompanied by increased levels of activated p38delta, and synergistic activation of p38delta by MLK3

11 caMEK6 also activates p38delta, but p38delta inhibits the caMEK6-dependent act

12 sent studies suggest that PKCdelta activates p38delta leading to increased p21(Cip1) promoter activit

13 keratinocyte differentiation that activates p38delta phosphorylation leading to increased differenti

14 ovel regulatory pathway involving CITED2 and p38delta, which may be critical for the maintenance of a

15 38gamma were involved in induction, ERK2 and p38delta played no role in TNF-alpha-dependent promoter

16 8alpha, which increases gene expression, and p38delta, which decreases gene expression.

17 MAPK (MAPK14) proteins p38gamma (MAPK12) and p38delta (MAPK13) were recently shown to modulate the im

18 p38alpha and p38delta are the most abundant isoforms expressed by all

19 activated the p38 MAPK isoforms p38alpha and p38delta in wild-type (Mkk3+/+) mesangial cells, but not

20 Thus, activation of p38alpha and p38delta is dependent on the activation of upstream MKK3

21 -state culture conditions, both p38alpha and p38delta isoforms are increasingly phosphorylated activa

22 tion is required for subsequent p38alpha and p38delta MAPK activation and collagen stimulation by TGF

23 st a critical role for the MKK3-p38alpha and p38delta MAPK pathway in mediating VEGF164 isoform-speci

24 However, opposing actions of p38alpha and p38delta negate any effect on TonEBP/OREBP activity.

25 of dominant negative mutants of p38alpha and p38delta resulted in marked inhibition of TGF-beta1-indu

26 In macrophages, p38alpha and p38delta were abundant, but p38beta was undetected.

27 p38alpha and p38delta were also expressed by neutrophils, CD4+ T cell

28 p38 MAPk isoforms studied, only p38alpha and p38delta were detected in neutrophils.

29 because of opposing effects of p38alpha and p38delta, and effects of inhibitors of p38 depend on whi

30 ctivation of p38 MAPK isoforms, p38alpha and p38delta, and stimulation of pro-alpha1(I) collagen by T

31 xplained by opposing effects of p38alpha and p38delta, both of which are activated by high NaCl and i

32 er MAP kinases including ERK2, p38alpha, and p38delta and showed little inhibitory activity against a

33 e positive and negative roles of p38beta and p38delta in AP-1 regulation, MKK6 stimulates AP-1-depend

34 her, our results establish that p38gamma and p38delta are central to colitis-associated colon cancer

35 Together, our results establish p38gamma and p38delta as key components in innate immune responses.

36 esponse to injury, and validate p38gamma and p38delta as potential targets for cancer therapy.

37 Here, we show that deletion of p38gamma and p38delta impaired the innate immune response to lipopoly

38 We analyzed the role of p38gamma and p38delta in colon cancer associated to colitis using the

39 owever, the role of the related p38gamma and p38delta kinases has remained unclear.

40 p38gamma and p38delta were necessary to maintain steady-state levels

41 in mammals (p38alpha, p38beta2, p38gamma and p38delta).

42 p38alpha, p38beta, p38gamma, and p38delta are four isoforms of p38 mitogen-activated prot

43 the first time that p38alpha, p38gamma, and p38delta down-regulate fibulin 3 expression.

44 ily, including ERK5, p38alpha, p38gamma, and p38delta, and that the activation of certain kinases act

45 specific for the combination of PKCdelta and p38delta and is not produced by replacing PKCdelta with

46 e apoptosis, promotes identical PKCdelta and p38delta-ERK1/2 activity changes, leading to similar mor

47 Protein kinase C delta (PKCdelta) and p38delta are key proteins in a cascade that stimulates k

48 53 is an intermediary in this regulation, as p38delta expression increases p53 mRNA, protein, and pro

49 embers, with p38beta higher in 3T3 cells but p38delta only detected in the EMT-6 line.

50 caMEK6 also activates p38delta, but p38delta inhibits the caMEK6-dependent activation.

51 e regulation of the focal adhesion kinase by p38delta in the human breast cell lines.

52 cell growth is synergistically regulated by p38delta isoform, whereas nuclear factor kappa B (NFsmal

53 In addition, concurrent p38delta activation and extracellular signal-regulated k

54 We further show that exogenously expressed p38delta increases p21(Cip1) mRNA and protein and that p

55 s define a previously unappreciated role for p38delta in breast cancer development and evolution by r

56 indings strongly suggest an in vivo role for p38delta in promoting cell proliferation and tumor devel

57 ylated, and FHF can serve as a substrate for p38delta in vitro.

58 This study implicates p38delta mitogen-activated protein kinase (MAPK) as a do

59 Importantly, p38delta and PKD1 conversely regulate PTEN activity in n

60 ced susceptibility to skin carcinogenesis in p38delta-null mice involves a defect in proliferative re

61 th lung metastasis; however, mice deleted in p38delta (PyMT/p38delta(-/-)) exhibited delayed primary

62 to IB2(Delta1-436) and can thereby increase p38delta interaction with IB2(Delta1-436).

63 PRMT5 knockdown is associated with increased p38delta phosphorylation, suggesting that PRMT5 impacts

64 tivated protein kinase (MAPK) delta isoform (p38delta) is a poorly studied member of the MAPK family.

65 Here, we show that p38 MAP kinase p38delta is required for recruitment of neutrophils into

66 The novel kinase, p38delta, has a nucleotide sequence encoding a protein o

67 In addition, cells lacking p38delta also displayed an increased cell-matrix adhesio

68 We report that mice lacking p38delta gene exhibited a marked resistance to developme

69 This study proposes MAPK p38delta protein as a key factor in breast cancer.

70 g to IB2 facilitates recruitment of the MAPK p38delta (SAPK4), while failing to stimulate binding of

71 , involucrin (hINV), via a Ras, MEKK1, MEK3, p38delta signaling cascade.

72 propose that PKCdelta activates a MEKK1/MEK3/p38delta MAPK cascade to increase p53 levels and p53 dri

73 ing module in which IB2 scaffolds a MLK3/MKK/p38delta kinase cascade.

74 Silencing of p38alpha, but not p38delta, using siRNA suppressed MDA-MB-468 cell prolife

75 ated p38delta, and synergistic activation of p38delta by MLK3 and IB2 is further enhanced by FHF2.

76 ation of p38alpha and a lesser activation of p38delta in LPS-stimulated macrophages.

77 ctive form of MEK6, an upstream activator of p38delta, can also produce cell death when coupled with

78 e other p38 isoforms, the kinase activity of p38delta is not blocked by the pyridinyl imidazole, 4-(4

79 2 minimally inhibited the kinase activity of p38delta.

80 Dot-blot analysis of p38delta mRNA in 50 human tissues revealed a distributio

81 Binding of p38delta to IB2 is mediated by the carboxyl-terminal hal

82 will be needed to define the contribution of p38delta to macrophage, neutrophil, and T cell functions

83 Global and myeloid-restricted deletion of p38delta in mice results in decreased alveolar neutrophi

84 resent study, we have assessed the effect of p38delta deficiency on skin tumor development in vivo by

85 nant form of p38 in monocytes; expression of p38delta was low and p38beta was undetected.

86 We demonstrate a direct interaction of p38delta with PKCdelta and MEK3 and show that exogenous

87 Also, siRNA-mediated knockdown of p38delta enhances the activation of TonEBP/OREBP.

88 Lack of p38delta resulted in reduced primary tumor size and bloc

89 TonEBP/OREBP activity, but overexpression of p38delta reduces it.

90 alpha, but primarily mono-phosphorylation of p38delta.

91 n tissues revealed a distribution profile of p38delta that differs from p38alpha.

92 FHF-induced recruitment of p38delta to IB2 is accompanied by increased levels of ac

93 ular level, we demonstrate that targeting of p38delta in breast cancer cells, MCF-7 and MDA-MB-231 re

94 duced by replacing PKCdelta with PKCalpha or p38delta with p38alpha.

95 In this model, PKCdelta or p38delta knockdown results in reduced p53 and p21(Cip1)

96 Like p38alpha, p38delta is activated by cellular stress and proinflamma

97 ng increases MKK4, which activates p38gamma, p38delta, and JNK2 to phosphorylate p53 on Ser-33 and ca

98 nine, the corresponding residue in p38gamma, p38delta, and the JNKs, rendered all five inhibitors ine

99 2, JNK3); p38s (p38alpha, p38beta, p38gamma, p38delta) and ERK5.

100 Silencing p38gamma, p38delta, or JNK2 partially rescued G(1) arrest from SEP

101 n cancer model in wild-type (WT), p38gamma-, p38delta-, and p38gamma/delta-deficient (p38gamma/delta(

102 es by MKK6 and/or arsenite, whereas p38gamma/p38delta inhibits or has no effect on the stimulation.

103 PKCdelta/p38delta signaling, a key controller of keratinocyte pro

104 understand the relationship between PKCdelta/p38delta and PRMT5/MEP50 signaling.

105 describe an opposing action between PKCdelta/p38delta MAPK signaling and PRMT5/MEP50 epigenetic silen

106 is an example of crosstalk between PKCdelta/p38delta signaling and PRMT5/MEP50 epigenetic silencing.

107 We further show that PKCdelta/p38delta signaling suppresses MEP50 expression, leading

108 We further show that the PKCdelta/p38delta keratinocyte differentiation cascade reduces PR

109 sis; however, mice deleted in p38delta (PyMT/p38delta(-/-)) exhibited delayed primary tumor formation

110 Reciprocally, p38delta overexpression induced IL-6 biosynthesis.

111 SAPK4/p38delta phosphorylated eEF2K at Ser359 in vitro, causin

112 cts that was phosphorylated rapidly by SAPK4/p38delta, but poorly by SAPK2/p38, SAPK3/p38gamma, SAPK1

113 expression of a catalytically inactive SAPK4/p38delta mutant, suggesting that SAPK4/p38delta may medi

114 st that activates all SAPKs, including SAPK4/p38delta.

115 SAPK4/p38delta mutant, suggesting that SAPK4/p38delta may mediate the inhibition of eEF2K by this str

116 skin tumor development in vivo by subjecting p38delta knockout mice to a two-stage 7,12-dimethylbenz(

117 itogen-activated protein kinases here termed p38delta.

118 ted to play an important role in terminating p38delta activation responsible for IL-6 biosynthesis.

119 ncreases p21(Cip1) mRNA and protein and that p38delta knockdown or expression of dominant-negative p3

120 a new member of the p38 MAPK family and that p38delta likely has functions distinct from that of p38a

121 This finding that p38delta isoform promotes the phosphorylation of ERK1/2

122 Taken together, these data indicate that p38delta is a new member of the p38 MAPK family and that

123 We also observed that p38delta was strongly activated by MKK3 and MKK6, while

124 Sequence comparisons revealed that p38delta is approximately 60% identical to the other thr

125 e Cancer Genome Atlas database revealed that p38delta is highly expressed in all types of human breas

126 The data presented herein show that p38delta has many properties that are similar to those o

127 Recent studies have shown that p38delta, a p38 family member, functions as an important

128 Our previous studies suggest that p38delta exists in association with protein partners.

129 se assays and inhibitor studies suggest that p38delta is the p38 isoform responsible for the regulati

130 Furthermore, the p38delta isoform was identified as a novel and predomina

131 orylation, suggesting that PRMT5 impacts the p38delta signaling complex.

132 sion, and PRMT5 dimethylates proteins in the p38delta complex.

133 e methyltransferase 5 (PRMT5) as part of the p38delta signaling complex.

134 , CITED2 up-regulation in vitro requires the p38delta isoform, which is specifically phosphorylated b

135 We further show that this p38delta-ERK1/2 complex relocates into the nucleus in re

136 The p38alpha to p38delta mitogen-activated protein kinases (MAPKs) are c

137 late differentiating erythroblasts, whereas p38delta mRNA is only expressed and active during the te

138 an also produce cell death when coupled with p38delta.

139 We show that coexpression of PKCdelta with p38delta produces profound apoptosis-like morphological