The Tumor Suppressor KLF11 Mediates a Novel Mechanism in Transforming Growth Factor β–Induced Growth Inhibition That Is Inactivated in Pancreatic Cancer

Buck, Andreas; Buchholz, Malte; Wagner, Martin; Adler, Guido; Gress, Thomas M.; Ellenrieder, Volker

doi:10.1158/1541-7786.mcr-06-0081

Cited by 51 publications

(45 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Through this key biochemical mechanism KLF11 regulates multiple cellular processes including cell growth, differentiation, apoptosis, endocrine disorders, and malignancy (Buck et al, 2006;Cook et al, 1998;Fernandez-Zapico et al, 2003;Tachibana et al, 1997). Relevant to the current study, we have previously shown that KLF11 (Fernandez-Zapico et al, 2003;Zhang et al, 2001) is a robust transcriptional activator for MAO B (Lu et al, 2008;Ou et al, 2004), increasing the transcription of this gene via distinct GC-rich sites, which are located adjacent to its transcription start sites (Ou et al, 2004).…”

Section: Introductionsupporting

confidence: 77%

“…KLF11 is known to inhibit cell growth (Buck et al, 2006;Cook et al, 1998), and increase oxidative stress (Neve et al, 2005) and apoptosis (Tachibana et al, 1997;Wang et al, 2007); which are mechanisms known to contribute to the development and progression of MDD. We hypothesized that KLF11 may be elevated in postmortem brain tissue from subjects with MDD because of the reduced prefrontal cortex volume, signs of cell death, and oxidative damage that have been KLF11-MAO a pathway in chronic stress and depressive disorders S Harris et al reported in the brains of depressive patients (Andreazza et al, 2010;Duman and Monteggia, 2006;Dwivedi et al, 2009), including patients with MDD (Duman and Monteggia, 2006;Dwivedi et al, 2009;Gawryluk et al, 2011;Kang et al, 2007).…”

Section: Upregulation Of the Klf11-mao A Pathway In The Prefrontal Comentioning

confidence: 99%

See 1 more Smart Citation

Evidence Revealing Deregulation of The KLF11-Mao A Pathway in Association with Chronic Stress and Depressive Disorders

Harris¹,

Johnson²,

Duncan

et al. 2014

Neuropsychopharmacol

View full text Add to dashboard Cite

The biochemical pathways underlying major depressive disorder (MDD) and chronic stress are not well understood. However, it has been reported that monoamine oxidase A (MAO A, a major neurotransmitter-degrading enzyme) is significantly increased in the brains of human subjects affected with MDD and rats exposed to chronic social defeat (CSD) stress, which is used to model depression. In the current study, we compared the protein levels of a MAO A-transcriptional activator, Kruppel-like factor 11 (KLF11 , also recognized as transforming growth factor-beta-inducible early gene 2) between the brains of 18 human subjects with MDD and 18 control subjects. We found that, indeed, the expression of KLF11 is increased by 36% (po0.02) in the postmortem prefrontal cortex of human subjects with MDD compared with controls. We also observed a positive correlation between KLF11 levels and those of its target gene, MAO A, both in association with MDD. KLF11 protein expression was also increased by 44% (po0.02) in the frontal cortex of KLF11 wild-type mice (Klf11 þ / þ ) vs Klf11 À / À when both exposed to CSD stress. In contrast, locomotor activities, central box duration and sucrose preference were significantly reduced in the stressed Klf11 þ / þ mice, suggesting that Klf11 þ / þ mice are more severely affected by the stress model compared with Klf11 À / À mice. These results serve to assign an important role of KLF11 in upregulating MAO A in MDD and chronic social stress, suggesting that inhibition of the pathways regulated by this transcription factor may aid in the therapeutics of neuropsychiatric illnesses. Thus, the new knowledge derived from the current study extends our understanding of transcriptional mechanisms that are operational in the pathophysiology of common human diseases and thus bears significant biomedical relevance.

show abstract

Section: Introductionsupporting

confidence: 77%

Section: Upregulation Of the Klf11-mao A Pathway In The Prefrontal Comentioning

confidence: 99%

Evidence Revealing Deregulation of The KLF11-Mao A Pathway in Association with Chronic Stress and Depressive Disorders

Harris¹,

Johnson²,

Duncan

et al. 2014

Neuropsychopharmacol

View full text Add to dashboard Cite

show abstract

“…This result suggests that the Myc degradation pathway can be saturated or inhibited by high levels of Myc, explaining why the amplification of the c-myc gene is a powerful oncogenic event (40). On the other hand, Myc is regulated at multiple levels, and it is possible that ca-STAT5A may engage other mechanisms that limit Myc activity, translation, or RNA levels (41)(42)(43)(44)(45). STAT5-induced senescence provides a model system to study the interplay among all Myccontrolling pathways.…”

Section: Discussionmentioning

confidence: 99%

Myc Down-regulation as a Mechanism to Activate the Rb Pathway in STAT5A-induced Senescence

Mallette

Gaumont-Leclerc

Huot

et al. 2007

Journal of Biological Chemistry

View full text Add to dashboard Cite

Senescence is a general antiproliferative program that avoids the expansion of cells bearing oncogenic mutations. We found that constitutively active STAT5A (ca-STAT5A) can induce a p53-and Rb-dependent cellular senescence response. However, ca-STAT5A did not induce p21 and p16INK4a , which are responsible for inhibiting cyclin-dependent protein kinases and engaging the Rb pathway during the senescence response to oncogenic ras. Intriguingly, ca-STAT5A led to a down-regulation of Myc and Myc targets, including CDK4, a negative regulator of Rb. The down-regulation of Myc was in part proteasome-dependent and correlated with its localization to promyelocytic leukemia bodies, which were found to be highly abundant during STAT5-induced senescence. Introduction of CDK4 or Myc bypassed STAT5A-induced senescence in cells in which p53 was also inactivated. These results uncover a novel mechanism to engage the Rb pathway in oncogene-induced senescence and indicate the existence of oncogene-specific pathways that regulate senescence.The Rb (retinoblastoma) family controls cell proliferation by providing a barrier for cell cycle transitions (1). In molecular terms, this barrier consists of repression of the E2F family of transcription factors, which control the synthesis of genes required for cell cycle progression (2). Growth factors activate the cyclin-dependent protein kinase (CDK) 2 -cyclin complexes that phosphorylate Rb, inhibiting its binding to E2F factors (1). Gain-of-function mutations in genes that stimulate cell cycle progression can potentially disable the Rb barrier, leading to tumorigenesis. Hence, for efficient tumor suppression, normal cells must avoid Rb inactivation by oncogenes. Studies on the senescent cell cycle arrest in response to oncogenic ras have provided a general model of Rb activation by oncogenes in normal cells. Aberrant ras activity induces the expression of CDK inhibitors of the INK4 family such as p15INK4b (3) (6). This allele was shown to be constitutively phosphorylated at tyrosine residues, localized to the nucleus, and transcriptionally active (7). Hence, ca-STAT5A provides a persistent and unregulated STAT5A signal similar to that observed in some human tumors (8, 9). We show here that ca-STAT5A engages the Rb pathway by down-regulating Myc instead of the p16 INK4a -mediated mechanism described in RasV12-induced senescence. As a consequence, cells expressing ca-STAT5 have a decrease in the expression of Myc targets such as CDK4 and an increase in the CDK inhibitor p15 INK4b. In agreement, ca-STAT5A-induced senescence is blocked when CDK4 or Myc is overexpressed in combination with dominant-negative p53 or the E6 protein of human papillomavirus. We conclude that the pathways regulating Rb by oncogenic signals are oncogene-specific and discuss the relevance of this concept for human cancers. EXPERIMENTAL PROCEDURESCells and Retroviruses-Normal human diploid fibroblasts (HDFs), BJ cells (obtained from Dr. S. W. Lowe), and IMR90 cells (American Type Culture Collection) were cultured in...

show abstract

“…In this context, the functions of Klf10 and Klf11 have been studied in several cells that are TGF-beta-sensitive. Most of these studies have demonstrated that Klf10 and Klf11 mimic the effects of TGF-beta either in promoting apoptosis (Tachibana et al 1997;Ribeiro et al 1999;Bender et al 2004;Wang et al 2007;Jin et al 2007;Gohla et al 2008) or in decreasing proliferation (Cook et al 1998;Hefferan et al 2000b;Fernandez-Zapico et al 2003;Buck et al 2006). The pro-apoptotic effects of Klf10 and Klf11 seem to involve the transcriptional regulation of members of the Bcl-2 family.…”

Section: Role Of Klf10 and Klf11 In Apoptosis And Cell Cycle Progressionmentioning

confidence: 99%

Klf10 and Klf11 as mediators of TGF-beta superfamily signaling

Spittau

Krieglstein

2011

Cell Tissue Res

View full text Add to dashboard Cite

Klf10 and Klf11 belong to the family of Sp1/Krüppel-like zinc finger transcription factors that play important roles in a variety of cell types and tissues. Although Klf10 and Klf11 were initially introduced as transforming growth factor-beta (TGF-beta)-inducible genes, several studies have described their upregulation by a plethora of growth factors, cytokines and hormones. Here, we review the current knowledge of the inductive cues for Klf10 and Klf11 and focus on their transcriptional regulation by members of the TGF-beta superfamily. We further summarize their involvement in the regulation of the TGF-beta signaling pathway and discuss their possible role as molecules mediating crosstalk between various signaling pathways. Finally, we provide an overview of the pro-apoptotic and anti-proliferative functions of Klf10 and Klf11.

show abstract

The Tumor Suppressor KLF11 Mediates a Novel Mechanism in Transforming Growth Factor β–Induced Growth Inhibition That Is Inactivated in Pancreatic Cancer

Cited by 51 publications

References 41 publications

Evidence Revealing Deregulation of The KLF11-Mao A Pathway in Association with Chronic Stress and Depressive Disorders

Evidence Revealing Deregulation of The KLF11-Mao A Pathway in Association with Chronic Stress and Depressive Disorders

Myc Down-regulation as a Mechanism to Activate the Rb Pathway in STAT5A-induced Senescence

Klf10 and Klf11 as mediators of TGF-beta superfamily signaling

Contact Info

Product

Resources

About