Full-length hdmX transcripts decrease following genotoxic stress

Markey, Michael P.; Berberich, Steven J.

doi:10.1038/onc.2008.266

Cited by 30 publications

(36 citation statements)

References 40 publications

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“…Specific forms of genotoxic stress, such as UV radiation, doxorubicin, and cisplatin can induce aberrant splicing of HDMX mRNA as well as promoting the degradation of the full-length HDMX mRNA, together resulting in the loss of expression of the full-length protein (31,32). These studies as well our original report first describing mdmx (9) have shown that total HDMX/mdmx mRNA abundance does not generally increase in response to DNA damage-induced p53 activation.…”

mentioning

confidence: 55%

HDMX-L Is Expressed from a Functional p53-responsive Promoter in the First Intron of the HDMX Gene and Participates in an Autoregulatory Feedback Loop to Control p53 Activity

Phillips

Teunisse

Lam

et al. 2010

Journal of Biological Chemistry

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The p53 regulatory network is critically involved in preventing the initiation of cancer. In unstressed cells, p53 is maintained at low levels and is largely inactive, mainly through the action of its two essential negative regulators, HDM2 and HDMX. p53 abundance and activity are up-regulated in response to various stresses, including DNA damage and oncogene activation. Active p53 initiates transcriptional and transcription-independent programs that result in cell cycle arrest, cellular senescence, or apoptosis. p53 also activates transcription of HDM2, which initially leads to the degradation of HDMX, creating a positive feedback loop to obtain maximal activation of p53. Subsequently, when stress-induced post-translational modifications start to decline, HDM2 becomes effective in targeting p53 for degradation, thus attenuating the p53 response. To date, no clear function for HDMX in this critical attenuation phase has been demonstrated experimentally. Like HDM2, the HDMX gene contains a promoter (P2) in its first intron that is potentially inducible by p53. We show that p53 activation in response to a plethora of p53-activating agents induces the transcription of a novel HDMX mRNA transcript from the HDMX-P2 promoter. This mRNA is more efficiently translated than that expressed from the constitutive HDMX-P1 promoter, and it encodes a long form of HDMX protein, HDMX-L. Importantly, we demonstrate that HDMX-L cooperates with HDM2 to promote the ubiquitination of p53 and that p53-induced HDMX transcription from the P2 promoter can play a key role in the attenuation phase of the p53 response, to effectively diminish p53 abundance as cells recover from stress.The tumor suppressor protein p53 functions primarily as a stress-inducible transcriptional activator of genes that promote cell cycle arrest and apoptosis (1). Stress-induced p53 activation can form a rate-limiting barrier to tumorigenesis (2, 3), and the manipulation of p53 function is key to the mechanism of action of many cancer chemotherapeutic strategies (4, 5). In unstressed cells, p53 is maintained at low levels and inactive, largely through the action of several p53-inducible negative feedback pathways, the most extensively studied of which involves the oncoproteins HDM2 and HDMX (also called MDM4) (MDM2 and MDMX/MDM4 in mice) (6, 7). Considerable research effort has been applied to understanding the mechanisms whereby these two proteins regulate p53 function. HDM2 and HDMX both contain an N-terminal pocket that binds to the primary transactivation domain of p53; they can, therefore, function independently of each other to repress p53-dependent transcription (8 -10). HDM2 also forms both HDM2-HDM2 homodimers and HDM2-HDMX heterodimers. These function as E3 ubiquitin ligases for p53; monoubiquitination of p53 by HDM2 inhibits p53 activity by both inhibiting acetylation and promoting nuclear export, whereas polyubiquitination promotes proteasome-mediated p53 degradation and is largely responsible for the rapid turnover of p53 protein that occurs in proli...

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mentioning

confidence: 55%

HDMX-L Is Expressed from a Functional p53-responsive Promoter in the First Intron of the HDMX Gene and Participates in an Autoregulatory Feedback Loop to Control p53 Activity

Phillips

Teunisse

Lam

et al. 2010

Journal of Biological Chemistry

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“…miR-34c belongs to a family of evolutionarily conserved miRNAs (miR-34a, miR-34b, and miR-34c) that have recently been shown to be involved in the negative control of the cell cycle (Corney et al 2007;Dutta et al 2007;He et al 2007;Raver-Shapira et al 2007;Lujambio et al 2008;Markey and Berberich 2008;Ji et al 2009), including cell cycle arrest (Paris et al 2008;Sun et al 2008), cellular senescence (He et al 2007;Tazawa et al 2007;Kumamoto et al 2008;Christoffersen et al 2009), and induction of apoptosis (Bommer et al 2007;Chang et al 2007;Raver-Shapira et al 2007;Welch et al 2007;Yamakuchi et al 2008). In these systems, some targets directly down-regulated by miR-34s have also been experimentally validated, and it appears that most of them are involved in pathways related to these cellular processes: NOTCH1, MET, E2F1-3, MYC, MYCN, CDK4, CDK6, CCND1, and CCNE2, and cell cycle, SIRT1, BCL2, and apoptosis, and viral oncoprotein E6 (Lewis et al 2003;Bommer et al 2007;He et al 2007;Tazawa et al 2007;Welch et al 2007;Kong et al 2008;Leucci et al 2008;Lujambio et al 2008;Migliore et al 2008;Sun et al 2008;Wei et al 2008;Yamakuchi et al 2008;Li et al 2009;Wang et al 2009).…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, a high level of miR-34c was present in adult pachytenes spermatocytes and round spermatids. This microRNA, miR-34c, belongs to a family of evolutionarily conserved miRNAs (miR-34a, miR-34b, and miR-34c), whose expression is regulated by the tumor suppressor protein p53 and are implicated in the negative control of the cell cycle (Corney et al 2007;Dutta et al 2007;He et al 2007;Raver-Shapira et al 2007;Lujambio et al 2008;Markey and Berberich 2008;Ji et al 2009), cell cycle arrest (Paris et al 2008;Sun et al 2008), senescence (He et al 2007;Tazawa et al 2007;Kumamoto et al 2008;Christoffersen et al 2009), and apoptosis (Bommer et al 2007;Chang et al 2007;Raver-Shapira et al 2007;Welch et al 2007;Yamakuchi et al 2008). However, the involvement of miR34c in the differentiation process has not yet been reported.…”

Section: Mir-34c Is Specifically Expressed In Germ Cellsmentioning

confidence: 99%

Role of miR-34c microRNA in the late steps of spermatogenesis

Bouhallier¹,

Allioli²,

Lavial³

et al. 2010

RNA

243

232

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Spermatogenesis is a cyclic process in which diploid spermatogonia differentiate into haploid spermatozoa. This process is highly regulated, notably at the post-transcriptional level. MicroRNAs (miRNAs), single-stranded noncoding RNA molecules of about 20-25 nucleotides, are implicated in the regulation of many important biological pathways such as proliferation, apoptosis, and differentiation. We wondered whether miRNAs could play a role during spermatogenesis. The miRNA expression repertoire was tested in germ cells, and we present data showing that miR-34c was highly expressed only in these cells. Furthermore, our findings indicate that in male gonads, miR-34c expression is largely p53 independent in contrast to previous results showing a direct link in somatic cells between the miR-34 family and this tumor suppressor protein. In order to identify target genes involved in germinal lineage differentiation, we overexpressed miR-34c in HeLa cells, analyzed the transcriptome of these modified cells, and noticed a shift of the expression profile toward the germinal lineage. Recently, it has been shown that exogenous expression of Ddx4/Vasa in embryonic chicken stem cells (cESC) induces cESC reprogramming toward a germ cell fate. When we simultaneously expressed miR-34c in such cells, we could detect an up-regulation of germ cell-specific genes whereas the expression of other lineage specific markers remained unchanged. These data suggest that miR-34c could play a role by enhancing the germinal phenotype of cells already committed to this lineage.

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“…3D; Supplemental Fig. S2H) and its important functions as one major negative regulator of p53 (Marine et al 2006;Markey and Berberich 2008;Mandke et al 2012;Wade et al 2013). mdm4/HDM4 and its closely related homolog, mdm2/HDM2, both encode RING domain proteins that promote oncogenesis by inhibiting p53 (Marine et al 2006;Wade et al 2013).…”

Section: Cold Springmentioning

confidence: 99%

A positive feedback between p53 and miR-34 miRNAs mediates tumor suppression

et al. 2014

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As bona fide p53 transcriptional targets, miR-34 microRNAs (miRNAs) exhibit frequent alterations in many human tumor types and elicit multiple p53 downstream effects upon overexpression. Unexpectedly, miR-34 deletion alone fails to impair multiple p53-mediated tumor suppressor effects in mice, possibly due to the considerable redundancy in the p53 pathway. Here, we demonstrate that miR-34a represses HDM4, a potent negative regulator of p53, creating a positive feedback loop acting on p53. In a Kras-induced mouse lung cancer model, miR-34a deficiency alone does not exhibit a strong oncogenic effect. However, miR-34a deficiency strongly promotes tumorigenesis when p53 is haploinsufficient, suggesting that the defective p53-miR-34 feedback loop can enhance oncogenesis in a specific context. The importance of the p53/miR-34/HDM4 feedback loop is further confirmed by an inverse correlation between miR-34 and full-length HDM4 in human lung adenocarcinomas. In addition, human lung adenocarcinomas generate an elevated level of a short HDM4 isoform through alternative polyadenylation. This short HDM4 isoform lacks miR-34-binding sites in the 39 untranslated region (UTR), thereby evading miR-34 regulation to disable the p53-miR-34 positive feedback. Taken together, our results elucidated the intricate cross-talk between p53 and miR-34 miRNAs and revealed an important tumor suppressor effect generated by this positive feedback loop.

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Full-length hdmX transcripts decrease following genotoxic stress

Cited by 30 publications

References 40 publications

HDMX-L Is Expressed from a Functional p53-responsive Promoter in the First Intron of the HDMX Gene and Participates in an Autoregulatory Feedback Loop to Control p53 Activity

HDMX-L Is Expressed from a Functional p53-responsive Promoter in the First Intron of the HDMX Gene and Participates in an Autoregulatory Feedback Loop to Control p53 Activity

Role of miR-34c microRNA in the late steps of spermatogenesis

A positive feedback between p53 and miR-34 miRNAs mediates tumor suppression

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