Gadd45a and Gadd45b Protect Hematopoietic Cells from UV-induced Apoptosis via Distinct Signaling Pathways, including p38 Activation and JNK Inhibition

Gupta, Mamta; Gupta, Shiv K.; Hoffman, Barbara; Liebermann, Dan A.

doi:10.1074/jbc.m600950200

Cited by 117 publications

(119 citation statements)

References 34 publications

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“…In turn, GADD45a was suggested to act in a positive feedback loop and to induce p38/MK2-dependent phosphorylation of cdc25B/C, binding of 14-3-3 protein and cytosolic sequestration of cdc25B/C . This finding is in line with the observation that the pro-survival activity of GADD45a in hematopoietic cells exposed to UV depends on the p38 pathway (Gupta et al, 2006). However, GADD45a was also reported to directly associate with and inhibit cyclin-B/Cdk1 Zhan et al, 1999), and thus it is possible that GADD45a prevents premature mitotic entry through multiple independent mechanisms.…”

Section: Checkpoint Maintenancesupporting

confidence: 79%

Checkpoint control and cancer

2011

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DNA-damaging therapies represent the most frequently used non-surgical anticancer strategies in the treatment of human tumors. These therapies can kill tumor cells, but at the same time they can be particularly damaging and mutagenic to healthy tissues. The efficacy of DNAdamaging treatments can be improved if tumor cell death is selectively enhanced, and the recent application of poly-(ADP-ribose) polymerase inhibitors in BRCA1/2-deficient tumors is a successful example of this. DNA damage is known to trigger cell-cycle arrest through activation of DNA-damage checkpoints. This arrest can be reversed once the damage has been repaired, but irreparable damage can promote apoptosis or senescence. Alternatively, cells can reenter the cell cycle before repair has been completed, giving rise to mutations. In this review we discuss the mechanisms involved in the activation and inactivation of DNA-damage checkpoints, and how the transition from arrest and cell-cycle re-entry is controlled. In addition, we discuss recent attempts to target the checkpoint in anticancer strategies.

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Section: Checkpoint Maintenancesupporting

confidence: 79%

Checkpoint control and cancer

2011

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“…Those findings were somewhat surprising, because, although Gadd45b was originally described as a pro-apoptotic protein in response to TGFb (Selvakumaran et al, 1994;Yoo et al, 2003), more recent results have revealed antiapoptotic functions for gadd45b. Importantly, however, these studies have only demonstrated an antiapoptotic function for Gadd45b in the extrinsic apoptotic pathway (induced by stimulation with TNFa or Fas ligand) (De Smaele et al, 2001;Zazzeroni et al, 2003) or have inferred an antiapoptotic function by evaluating genotoxic-stressinduced apoptosis in gadd45b À/À bone marrow cells (Gupta et al, 2005(Gupta et al, , 2006. In accordance with our data, other work demonstrated that Gadd45b does not have an influence on apoptosis (Zerbini et al, 2004).…”

Section: Discussionsupporting

confidence: 81%

Gadd45β is a pro-survival factor associated with stress-resistant tumors

et al. 2007

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“…GADD45␤ protein is known to bind to MTK1/MEKK4, a MAP3K, leading to the phosphorylation of MAP2Ks, such as MKK3 or -6 and MKK4 or -7, followed by activation of the p38 and JNK pathways, respectively (10 -12). However, interaction of GADD45␤ with MTK1 has been reported to inhibit or activate MKK7, followed by inhibition or activation of JNK signaling, depending on the cell type and the availability of upstream signals, such as NF-B (13)(14)(15)(16)(17). In chondrocytes, we found that GADD45␤ via JNK activation increased MMP13 promoter activity in synergism with Fra1 or Fra2 together with JunB or JunD (8).…”

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confidence: 48%

GADD45β Enhances Col10a1 Transcription via the MTK1/MKK3/6/p38 Axis and Activation of C/EBPβ-TAD4 in Terminally Differentiating Chondrocytes

Tsuchimochi

Otero

Dragomir

et al. 2010

Journal of Biological Chemistry

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GADD45␤ (growth arrest-and DNA damage-inducible) interacts with upstream regulators of the JNK and p38 stress response kinases. Previously, we reported that the hypertrophic zone of the Gadd45␤ ؊/؊ mouse embryonic growth plate is compressed, and expression of type X collagen (Col10a1) and matrix metalloproteinase 13 (Mmp13) genes is decreased. Herein, we report that GADD45␤ enhances activity of the proximal Col10a1 promoter, which contains evolutionarily conserved AP-1, cAMP-response element, and C/EBP half-sites, in synergism with C/EBP family members, whereas the MMP13 promoter responds to GADD45␤ together with AP-1, ATF, or C/EBP family members. C/EBP␤ expression also predominantly co-localizes with GADD45␤ in the embryonic growth plate. Moreover, GADD45␤ enhances C/EBP␤ activation via MTK1, MKK3, and MKK6, and dominant-negative p38␣apf, but not JNKapf, disrupts the combined trans-activating effect of GADD45␤ and C/EBP␤ on the Col10a1 promoter. Importantly, GADD45␤ knockdown prevents p38 phosphorylation while decreasing Col10a1 mRNA levels but does not affect C/EBP␤ binding to the Col10a1 promoter in vivo, indicating that GADD45␤ influences the transactivation function of DNA-bound C/EBP␤. In support of this conclusion, we show that the evolutionarily conserved TAD4 domain of C/EBP␤ is the target of the GADD45␤-dependent signaling. Collectively, we have uncovered a novel molecular mechanism linking GADD45␤ via the MTK1/MKK3/6/p38 axis to C/EBP␤-TAD4 activation of Col10a1 transcription in terminally differentiating chondrocytes.

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Gadd45a and Gadd45b Protect Hematopoietic Cells from UV-induced Apoptosis via Distinct Signaling Pathways, including p38 Activation and JNK Inhibition

Cited by 117 publications

References 34 publications

Checkpoint control and cancer

Checkpoint control and cancer

Gadd45β is a pro-survival factor associated with stress-resistant tumors

GADD45β Enhances Col10a1 Transcription via the MTK1/MKK3/6/p38 Axis and Activation of C/EBPβ-TAD4 in Terminally Differentiating Chondrocytes

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