<i>Gadd45a</i> Functions as a Promoter or Suppressor of Breast Cancer Dependent on the Oncogenic Stress

Tront, Jennifer S.; Huang, Yajue; Fornace, Albert J.; Hoffman, Barbara; Liebermann, Dan A.

doi:10.1158/0008-5472.can-10-2177

Cited by 57 publications

(49 citation statements)

References 26 publications

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“…We demonstrated that Gadd45a feeds into the Jnk-dependent signaling pathway to activate p53 when bcatenin is active. Consistent with this observation, Gadd45a deletion accelerates Ras-and Myc-driven mammary tumor formation, potentially through regulation of Jnk-induced apoptosis, 29,35 while MKK7-Jnk signaling pathway is required for activation of p53 in several mouse models of cancer. 30 It is important to note that Gadd45a deletion specifically affected b-catenin-induced activation but did not completely inactivate the Jnk-dependent signaling pathway.…”

Section: Discussionsupporting

confidence: 63%

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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Section: Discussionsupporting

confidence: 63%

Role of Gadd45a in Wip1-dependent regulation of intestinal tumorigenesis

et al. 2012

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“…The roles of GADD45a, PTPRV, PML, and CAV1 have been examined individually through the generation of knockout mice but none of these animals spontaneously develop cancer (Hollander et al 1999;Razani et al 2001;Rego et al 2001;Doumont et al 2005). However, similar to other candidate TP53 tumor-suppressor transcriptional targets, their deficiency can accelerate tumor formation under conditions of specific oncogenic stress (Capozza et al 2003;Tront et al 2010).…”

Section: Cell-cycle Regulation and Dnadamage Repairmentioning

confidence: 99%

Tumor-Suppressor Functions of the TP53 Pathway

Aubrey

Strasser

Kelly

2016

Cold Spring Harb Perspect Med

231

157

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The fundamental biological importance of the Tp53 gene family is highlighted by its evolutionary conservation for more than one billion years dating back to the earliest multicellular organisms. The TP53 protein provides essential functions in the cellular response to diverse stresses and safeguards maintenance of genomic integrity, and this is manifest in its critical role in tumor suppression. The importance of Tp53 in tumor prevention is exemplified in human cancer where it is the most frequently detected genetic alteration. This is confirmed in animal models, in which a defective Tp53 gene leads inexorably to cancer development, whereas reinstatement of TP53 function results in regression of established tumors that had been initiated by loss of TP53. Remarkably, despite extensive investigation, the specific mechanisms by which TP53 acts as a tumor suppressor are yet to be fully defined. We review the history and current standing of efforts to understand these mechanisms and how they complement each other in tumor suppression.T he TP53 protein is a critical tumor suppressor that plays a fundamental and multifaceted role in the development of cancer and cancer therapy. Despite more than 30 years of vigorous research and an expansive body of literature, the precise molecular mechanism underlying TP53's tumor-suppressor function has not been defined and remains the focus of active investigation. Understanding the tumorsuppressor function of the Tp53 gene will not only have profound importance to the understanding of cancer biology but will likely have an impact on cancer therapy and prevention through improved exploitation of wild-type Tp53 functions as well as gained insight into specific vulnerabilities imposed on tumors by loss of TP53 function. The TP53 protein exerts effector functions that impact on virtually all of the hallmark features of cancer (Hanahan and Weinberg 2011); however, it is still not clear which of these functions is essential to its potent tumor-suppressor function and how these functions interact. Indeed, it is becoming increasingly apparent that multiple pathways are likely to collaborate in exerting this tumor-suppression function and that the TP53 protein has context-specific roles. Here we discuss the functioning of the TP53 protein as a tumor suppresEditors:

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“…GADD45A has been reported to have the dual and seemingly conflicting functions of tumor promotion and tumor suppression with the outcome being highly dependent on the oncogenic stimuli. 52 Moderate DNA damage can trigger GADD45A to exert an antiapoptotic function, binding to other proteins to enhance DNA repair, whereas excessive DNA damage may act as a prompt for apoptosis, possibly acting as a survival mechanism during situations where irreparable cell damage is evident. 53 FLT3LG is a critical transmembrane protein well documented to stimulate the proliferation of hematopoietic cells.…”

Section: Discussionmentioning

confidence: 99%

Changes in Whole Blood Gene Expression after Computed Tomography in Children: A Pilot Study

Lai¹,

Halm²,

Tiirikainen³

et al. 2015

GGG

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ABSTRACT:Computed tomography (CT) exposes patients to ionizing X-irradiation (IR) that can alter the expression of genes responsible for controlling complex regulatory pathways. We sought to determine trends in the expression of 24 documented radiation-responsive genes linked to cancer in vivo. A total of 17 children (0.25-6 years old) undergoing medically indicated CT examinations with radiation doses ranging from 92.46 to 525.55 mGy cm (equivalent to effective doses of 0.78-11.30 mSv) were enrolled. Blood was drawn immediately before and 1 hour after their CT exams and mixed with an RNA additive for stabilization of gene expression. RNA samples of 14 of the 17 children were analyzed on a gene expression microarray. Absolute changes in gene expression were subtle, averaging less than 10%, but trends in expression changes of several genes were observed. ERP29, an endoplasmic reticulum chaperone, thought to be involved in the folding of secretory proteins, showed significant change in expression (8% decrease, P = 0.002) in the expected direction consistent with previous literature. PCNA expression increased linearly with CT dose (mGy cm) (P = 0.001). TP53 and FLT3LG expression increased linearly with effective dose (mSv) (P = 0.02 and P = 0.02). Previous IR exposure was associated with decreased GADD45A (P = 0.001) and FLT3LG (P = 0.03) and increased MDM2 expression (P = 0.02). We observed in this pilot study modest gene expression changes in the 24 IR-responsive candidate genes studied. Our results showed trends in gene expression changes, and they need to be confirmed in future studies with larger sample sizes to help develop risk assessments and preventive modalities for young patients undergoing CT.

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Gadd45a Functions as a Promoter or Suppressor of Breast Cancer Dependent on the Oncogenic Stress

Cited by 57 publications

References 26 publications

Role of Gadd45a in Wip1-dependent regulation of intestinal tumorigenesis

Role of Gadd45a in Wip1-dependent regulation of intestinal tumorigenesis

Tumor-Suppressor Functions of the TP53 Pathway

Changes in Whole Blood Gene Expression after Computed Tomography in Children: A Pilot Study

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