p38MAPK Controls Expression of Multiple Cell Cycle Inhibitors and Islet Proliferation with Advancing Age

Wong, Esther; Guezennec, Xavier Le; Demidov, Oleg N.; Marshall, Nicolette Theresa; Wang, Siew Tein; Krishnamurthy, Janakiraman; Sharpless, Norman E.; Dunn, N. Ray; Bulavin, Dmitry V.

doi:10.1016/j.devcel.2009.05.009

Cited by 107 publications

(136 citation statements)

References 28 publications

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“…All animal protocols used in this study were approved by the Institute of Molecular and Cell Biology Animal Safety and Use Committee. To generate P224I knock-in mice the targeting vector described in Wong et al 50 was used that contained the equivalent of 4.5 kb of mouse DNA with an exon containing the Pro224 sites of p38MAPK. This site was mutated to isoleucine by site-directed mutagenesis (SDM primers: 5′-GCTGGTT AATATGGTCTGTACCAATAAACAACGTTCTTCCGGTC-3′; 5′-GACCGGAAGAACG TTGTTTATTGGTACAGACCATATTAACCAGC-3').…”

Section: Discussionmentioning

confidence: 99%

Proline isomerisation as a novel regulatory mechanism for p38MAPK activation and functions

et al. 2016

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The stress-induced p38 mitogen-activated protein kinase (MAPK) pathway plays an essential role in multiple physiological processes, including cancer. In turn, p38MAPK phosphorylation at Thr180 and Tyr182 is a key regulatory mechanism for its activation and functions. Here we show that this mechanism is actively regulated through isomerisation of Pro224. Different cyclophilins can isomerise this proline residue and modulate the ability of upstream kinases to phosphorylate Thr180 and Tyr182. In vivo mutation of Pro224 to Ile in endogenous p38MAPK significantly reduced its phosphorylation and activity. This resulted in attenuation of p38MAPK signalling, which in turn caused an enhanced apoptosis and sensitivity to a DNA-damaging drug, cisplatin. We further found a reduction in size and number of lesions in homozygous mice carrying the p38MAPK P224I substitution in a K-ras model of lung tumorigenesis. We propose that cyclophilin-dependent isomerisation of p38MAPK is an important novel mechanism in regulating p38MAPK phosphorylation and functions. Thus, inhibition of this process, including with drugs that are in clinical trials, may improve the efficacy of current anti-cancer therapeutic regimes.

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Section: Discussionmentioning

confidence: 99%

Proline isomerisation as a novel regulatory mechanism for p38MAPK activation and functions

et al. 2016

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“…Wip1 expression has been shown to decrease with age in pancreatic islets and in neural stem/progenitor cells 23,26 . To examine the expression levels of Wip1 mRNA in HSCs and HPCs, we purified long-term (LT) HSCs, short-term (ST) HSCs, multipotent progenitors and lineage-committed progenitors (common lymphoid progenitors; common myeloid progenitors; megakaryocyte-erythroid progenitors; and granulocyte-macrophage progenitors) from young (2-to 3-month-old) and old (20-to 24-month-old) WT mice via fluorescence-activated cell sorting (FACS), as depicted in Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Recent studies suggest that Wip1 plays an important role in regulating certain physiological and pathological processes by dephosphorylating distinct downstream targets 21,[24][25][26]29,37 . In pancreatic islets, reduced Wip1 expression contributes to the aging-related decline in the proliferation and regenerative capacities of pancreatic islets via increased p38 activity 26 .…”

Section: Discussionmentioning

confidence: 99%

“…Wip1-deficient (Wip1 À / À ) mice exhibit varied phenotypes including tumour resistance 21,22 , impaired adult neurogenesis 23,24 , obesity, atherosclerosis 25 and premature aging 26,27 . In the haematopoietic system, Wip1 deletion in mice results in a smaller thymus due to p53-dependent cell cycle arrest during the development of T cells 28 and enhanced maturation of neutrophils, which are mediated by p38 MAPK-STAT1-dependent pathways 29 .…”

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confidence: 99%

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Wip1 deficiency impairs haematopoietic stem cell function via p53 and mTORC1 pathways

Chen

Morita

et al. 2015

Nat Commun

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Wild-type p53-induced phosphatase 1 (Wip1) negatively regulates several tumour suppressor and DNA damage response pathways. However, the impact of Wip1 on haematopoietic stem cell (HSC) homeostasis and aging remains unknown. Here we show that Wip1 is highly expressed in HSCs but decreases with age. Wip1-deficient (Wip1 À / À ) mice exhibited multifaceted HSC aging phenotypes, including the increased pool size and impaired repopulating activity. Deletion of p53 rescued the multilineage repopulation defect of Wip1 À / À HSCs without affecting cellular senescence or apoptosis, indicating that the Wip1-p53 axis regulates HSC differentiation in a manner independent of conventional p53 pathways. However, p53 deletion did not influence the increased HSC pool size in Wip1 À / À mice. Interestingly, the expansion of HSCs in Wip1 À / À mice was due to an mTORC1-mediated HSC proliferation. Thus, our study reveals a mechanism of stem cell aging, in which distinct effects of p53 and mTORC1 pathways on HSC aging are governed by Wip1.

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“…To downregulate p38MAPK in Wip1-deficient mice, we used a knock-in mouse strain expressing the dominant-negative p38 KI/ þ allele. 18 We further decided to evaluate Gadd45a-deficient mice, as Gadd45a participates in regulation of the p38Mapk-and Jnk-dependent signaling pathways. [19][20][21] In turn, Jnk is an important regulator of p53 and apoptosis under various conditions.…”

Section: Resultsmentioning

confidence: 99%

Role of Gadd45a in Wip1-dependent regulation of intestinal tumorigenesis

et al. 2012

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Conversion of intestinal stem cells into tumor-initiating cells is an early step in Apc Min -induced polyposis. Wild-type p53-induced phosphatase 1 (Wip1)-dependent activation of a DNA damage response and p53 has a permanent role in suppression of stem cell conversion, and deletion of Wip1 lowers the tumor burden in Apc Min mice. Here we show that cyclin-dependent kinase inhibitor 2a, checkpoint kinase 2, and growth arrest and DNA damage gene 45a (Gadd45a) exert critical functions in the tumor-resistant phenotype of Wip1-deficient mice. We further identified Gadd45a as a haploinsufficient gene in the regulation of Wip1-dependent tumor resistance in mice. Gadd45a appears to function through its ability to activate the Jnk-dependent signaling pathway that in turn is a necessary mediator of the proapoptotic functions of p53 that respond to activation of the b-catenin signaling pathway. We propose that silencing of Gadd45a is sufficient to override p53 activation in the presence of active b-catenin under conditions of an enhanced DNA damage response. Cell Death and Differentiation (2012) 19, 1761-1768 doi:10.1038/cdd.2012; published online 4 May 2012Conversion of normal cells into tumor-initiating cells is an initial step in the course of formation of any tumor. 1 The majority of cells in an organism are terminally differentiated and thus are not capable of conversion into tumor-initiating cells, which requires cellular proliferation. In many instances, proliferative progenitors are programmed to divide only a few times before full differentiation; acquiring oncogenic mutations at this stage may also have a limited impact on tumorigenesis unless the mutation blocks differentiation. Increasing evidence in turn indicates that certain types of cancers originate from adult stem cells, the only proliferative cells that exist in the animal for a significant period of time that may be sufficient to accumulate oncogenic mutations. Several studies have demonstrated the role of adult stem cells as an origin of cancer, at least in certain tissues such as mouse intestine. 2 Stem cell-specific inactivation of Apc (adenomatous polyposis coli ), the major regulator of tumorigenesis in the intestine, results in full-blown polyposis within a few weeks. 3 In contrast, deletion of Apc in proliferative progenitors or more differentiated cell types fails to induce sustainable cancer. 3 In many instances, activation of oncogenes in normal cells sets off the defense mechanisms to protect them from potential transformation. 4 The major pathway that has had evolved to perform this function is controlled by a tumor suppressor p53. Depending on the strength of the signal, which in many cases relies on the type of oncogene, p53 activates apoptosis, transient or permanent cell cycle arrest called senescence. 5 Modulation of p53 levels and activity may therefore be critical to the regulation of cell susceptibility to oncogenic transformation. Regulation of p53 by various means to prevent oncogenic transformation may be especially important when ...

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p38MAPK Controls Expression of Multiple Cell Cycle Inhibitors and Islet Proliferation with Advancing Age

Cited by 107 publications

References 28 publications

Proline isomerisation as a novel regulatory mechanism for p38MAPK activation and functions

Proline isomerisation as a novel regulatory mechanism for p38MAPK activation and functions

Wip1 deficiency impairs haematopoietic stem cell function via p53 and mTORC1 pathways

Role of Gadd45a in Wip1-dependent regulation of intestinal tumorigenesis

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