Suppression of PTEN Expression Is Essential for Antiapoptosis and Cellular Transformation by Oncogenic Ras

Vasudevan, Krishna Murthi; Burikhanov, Ravshan; Goswami, Anindya; Rangnekar, Vivek M.

doi:10.1158/0008-5472.can-07-1827

Cited by 63 publications

(73 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Accordingly, the PTEN and c-Jun levels inversely correlate in a panel of tumor cell lines. Although c-Jun was shown to inhibit the PTEN promoter, the PTEN 5 0 -flanking region targeted by c-Jun was not identified unambiguously (Hettinger et al, 2007;Vasudevan et al, 2007). In our RAS-inducible cell system, transcriptional inhibition does not seem to play a major role in the downregulation of PTEN, as the effect of RAS is entirely relieved by the inhibition of miR-21 (Figure 7c) affecting PTEN at the post-transcriptional level (Meng et al, 2007).…”

Section: Discussionmentioning

confidence: 74%

“…During tumorigenesis, AP-1 regulates a wide variety of target genes, positively controlling cell proliferation, invasion and angiogenesis (Eferl and Wagner, 2003;Ozanne et al, 2007) On the other hand, cell cycle inhibitory and proapoptotic tumor suppressors, such as p16 INK4A and PTEN, are usually repressed by c-Jun/AP-1 (Bakiri et al, 2000;Hettinger et al, 2007;Vasudevan et al, 2007). Although the AP-1-induced promoters are controlled by AP-1 binding to TRE elements, the genes inhibited by AP-1 do not share a common regulatory mechanism, thus suggesting the role of indirect control networks in AP-1-mediated gene repression.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

An autoregulatory loop mediated by miR-21 and PDCD4 controls the AP-1 activity in RAS transformation

et al. 2008

View full text Add to dashboard Cite

The transcription factor AP-1 plays key roles in tumorigenesis, by regulating a variety of protein-coding genes, implicated in multiple hallmarks of cancer. Among non-coding genes, no AP-1 target has been described yet in tumorigenesis. MicroRNAs (miRNAs) are negative post-transcriptional regulators of protein-coding genes. miRNA expression signatures are highly relevant in cancer and several tumor-associated miRNAs (oncomirs) play critical roles in oncogenesis. Here, we show that the miRNA miR-21, which represents the most frequently upregulated oncomir in solid tumors, is induced by AP-1 in response to RAS. By analyzing validated miR-21 targets, we have found that the tumor suppressors PTEN and PDCD4 are downregulated by RAS in an AP-1-and miR-21-dependent fashion. We further show that, given the role of PDCD4 as negative regulator of AP-1, the miR-21-mediated downregulation of PDCD4 is essential for the maximal induction of AP-1 activity in response to RAS. Our data reveal a novel mechanism of positive autoregulation of the AP-1 complex in RAS transformation and disclose the function of oncomirs as critical targets and regulators of AP-1 in tumorigenesis.

show abstract

Section: Discussionmentioning

confidence: 74%

Section: Introductionmentioning

confidence: 99%

An autoregulatory loop mediated by miR-21 and PDCD4 controls the AP-1 activity in RAS transformation

et al. 2008

View full text Add to dashboard Cite

show abstract

“…Physiologically, PTEN-dependent early endodermal morphogenesis seems to require the Erk, but not the Akt, pathway (36). Furthermore, in Rasinduced oncogenic transformation, PTEN apoptotic function is suppressed via the Raf-Mek-Erk pathway (37). Recent publications using human breast cancer cell lines support the notion that PI3K inhibition can involve an ERK-dependent component (38,39).…”

Section: Discussionmentioning

confidence: 99%

Pten loss promotes MAPK pathway dependency in HER2/neu breast carcinomas

Ebbesen

Scaltriti

Bialucha

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Loss of the tumor suppressor gene PTEN is implicated in breast cancer progression and resistance to targeted therapies, and is thought to promote tumorigenesis by activating PI3K signaling. In a transgenic model of breast cancer, Pten suppression using a tetracyclineregulatable short hairpin (sh)RNA cooperates with human epidermal growth factor receptor 2 (HER2/neu), leading to aggressive and metastatic disease with elevated signaling through PI3K and, surprisingly, the mitogen-activated protein kinase (MAPK) pathway. Restoring Pten function is sufficient to down-regulate both PI3K and MAPK signaling and triggers dramatic tumor regression. Pharmacologic inhibition of MAPK signaling produces similar effects to Pten restoration, suggesting that the MAPK pathway contributes to the maintenance of advanced breast cancers harboring Pten loss.

show abstract

“…16 -18 Interestingly, although there was a mild increase in the expression of total Rap1b, its GTP activity was reduced under high-glucose ambience, which probably was due to increased expression of GAP (Figures 1 and 2). Because Rap1b-related oncogenic Ras and Raf suppress the apoptotic gene PTEN via the Raf-MEK-extracellular signalregulated kinase-c-Jun pathway to induce cellular transformation and growth, 31 it may mean that Rap1b may exert a protective role in the scenario of glucose-induced injury leading to apoptosis. This seems to be the case because transfection of Rap1b resulted in the normalization of Bcl-2 and Bax expression, mitochondrial ⌬⌿ m with reduction in the leakage of cytochrome C, mtDNA damage, and apoptosis (Figures 2 through 4).…”

Section: Discussionmentioning

confidence: 99%

Rap1b GTPase Ameliorates Glucose-Induced Mitochondrial Dysfunction

Sun

Xie²,

Wada

et al. 2008

Journal of the American Society of Nephrology

View full text Add to dashboard Cite

The role of tubular injury in diabetic nephropathy is relatively unknown, despite that apoptosis of tubular epithelial cells is commonly observed in human renal biopsies. The GTPase Ras-proximate-1 (Rap1b) is upregulated in the hyperglycemic state and is known to increase B-Raf, an antiapoptotic effector protein.In this study, the effects of high glucose on renal tubular apoptosis and the potential ability for Rap1b to ameliorate these effects were investigated. In the kidneys of diabetic mice, apoptotic tubular cells and dysmorphic mitochondria were observed, Bcl-2 expression was decreased, and Bax expression was increased. Total Rap1b expression was slightly increased, but its associated GTPase activity was significantly decreased. In vitro, high extracellular glucose led to decreased Bcl-2 expression, reduced Rap1b GTPase activity, and increased levels of both Bax and GTPase activating protein in a proximal tubular cell line (HK-2). These changes were accompanied by increased DNA fragmentation, decreased high molecular weight mitochondrial DNA, altered mitochondrial morphology and function, disrupted Bcl-2-Bax and Bcl-2-Rap1b interactions, and reduced cell survival. Overexpression of Rap1b partially prevents these abnormalities. Furthermore, the BH4 domain of Bcl-2 was found to be required for successful protein-protein interaction between Bcl-2 and Rap1b. In summary, these data suggest that Rap1b ameliorates glucose-induced mitochondrial dysfunction in renal tubular cells.

show abstract

Suppression of PTEN Expression Is Essential for Antiapoptosis and Cellular Transformation by Oncogenic Ras

Cited by 63 publications

References 33 publications

An autoregulatory loop mediated by miR-21 and PDCD4 controls the AP-1 activity in RAS transformation

An autoregulatory loop mediated by miR-21 and PDCD4 controls the AP-1 activity in RAS transformation

Pten loss promotes MAPK pathway dependency in HER2/neu breast carcinomas

Rap1b GTPase Ameliorates Glucose-Induced Mitochondrial Dysfunction

Contact Info

Product

Resources

About