Positive correlation between overexpression of phospho-BAD with phosphorylated Akt at serine 473 but not threonine 308 in colorectal carcinoma

Khor, Tin Oo; Gul, Yunus A.; Ithnin, Hairuszah; Seow, Heng Fong

doi:10.1016/j.canlet.2004.01.017

Cited by 41 publications

(33 citation statements)

References 34 publications

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“…For example, analysis of the Bad coding region in colon adenocarcinomas indicated somatic mutations in 4.3% of the samples that reduced the apoptotic activity of BAD and mapped to its BH3 domain (E113K and L114F, corresponding to E150 and L151 in the murine BAD sequence) . Other studies have reported a significant increase in phosphorylated BAD in B60% of colorectal carcinomas, which showed positive correlation with high levels of phosphorylated AKT in some cases (Khor et al, 2004;Kim et al, 2007).…”

Section: Bad and Tumor Cell Apoptosismentioning

confidence: 70%

BAD: undertaker by night, candyman by day

2008

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The BH3-only pro-apoptotic proteins are upstream sensors of cellular damage that selectively respond to specific, proximal death and survival signals. Genetic models and biochemical studies indicate that these molecules are latent killers until activated through transcriptional or post-translational mechanisms in a tissue-restricted and signal-specific manner. The large number of BH3-only proteins, their unique subcellular localization, protein-interaction network and diverse modes of activation suggest specialization of their damage-sensing function, ensuring that the core apoptotic machinery is poised to receive input from a wide range of cellular stress signals. The apoptotic response initiated by the activation of BH3-only proteins ultimately culminates in allosteric activation of pro-apoptotic BAX and BAK, the gateway proteins to the mitochondrial pathway of apoptosis. From activation of BH3-only proteins to oligomerization of BAX and BAK and mitochondrial outer membrane permeabilization, an intricate network of interactions between the pro-and anti-apoptotic members of the BCL-2 family orchestrates the decision to undergo apoptosis. Beyond regulation of apoptosis, multiple BCL-2 proteins have recently emerged as active components of select homeostatic pathways carrying other cellular functions. This review focuses on BAD, which was the first BH3-only protein linked to proximal survival signals through phosphorylation by survival kinases. In addition to findings that delineated the physiological role of BAD in apoptosis and its dynamic regulation by phosphorylation, studies pointing to new roles for this protein in other physiological pathways, such as glucose metabolism, are highlighted. By executing its 'day' and 'night' jobs in metabolism and apoptosis, respectively, BAD helps coordinate mitochondrial fuel metabolism and the apoptotic machinery.

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Section: Bad and Tumor Cell Apoptosismentioning

confidence: 70%

BAD: undertaker by night, candyman by day

2008

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“…Ser473, but not at Thr308, has been reported in colorectal cancer (46). In our previous study, phospho-Akt expression was increased in Bcl-2 -negative FL as well as Bcl-2 -positive FL (9).…”

Section: Discussionmentioning

confidence: 95%

Proteomic Analysis of Apoptotic Pathways Reveals Prognostic Factors in Follicular Lymphoma

Gulmann

Espina

Petricoin

et al. 2005

Clinical Cancer Research

102

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Follicular lymphoma (FL) is the second most common non-Hodgkin's lymphoma and generally is incurable. Reliable prognostic markers to differentiate patients who progress rapidly from those who survive for years with indolent disease have not been established. Most cases overexpress Bcl-2, but the pathogenesis of FL remains incompletely understood. To determine whether a proteomic approach could help overcome these obstacles, we procured lymphoid follicles from 20 cases of FL and 15 cases of benign follicular hyperplasia (FH) using laser capture microdissection. Lysates were spotted on reverse-phase protein microarrays and probed with 21antibodies to proteins in the intrinsic apoptotic pathway, including those specific for posttranslational modifications such as phosphorylation. A panel of three antibodies [phospho-Akt(Ser473), Bcl-2, and cleaved poly(ADP-ribose) polymerase] segregated most cases of FL from FH. PhosphoAkt(Ser473) and Bcl-2 were significantly increased in FL (P = 0.001and P < 0.0001, respectively). Additionally, the Bcl-2/Bak ratio completely segregated FL from FH. High ratios of Bcl-2/Bak and Bcl-2/Bax were associated with early death from disease with differences in median survival times of 7.3 years (P = 0.0085) and 3.8 years (P = 0.018), respectively. Using protein microarrays, we identified candidate proteins that may signify clinically relevant molecular events in FL. This approach showed significant changes at the posttranslational level, including Akt phosphorylation, and suggested new prognostic markers, including the Bcl-2/Bak and Bcl-2/Bax ratios. Proteomic end points should be incorporated in larger, multicenter trials to validate the clinical utility of these protein microarray findings.

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“…This implies that regulation of PTEN phosphorylation in WT cells may aid in protecting the cells by maintaining the balance between proliferative and antiproliferative functions. It has been reported that there is a positive correlation between hyperactivated Akt(Ser(P) 473 ) and pathologic progression of cancer in colorectal carcinoma (48). PTEN, originally identified as a tumor suppressor protein, was found to be inactivated in several types of tumors (e.g.…”

Section: Discussionmentioning

confidence: 99%

A Novel Function of Plasminogen Activator Inhibitor-1 in Modulation of the AKT Pathway in Wild-type and Plasminogen Activator Inhibitor-1-deficient Endothelial Cells

Balsara

Castellino

Ploplis

2006

Journal of Biological Chemistry

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Cell proliferation, an event associated with angiogenesis, involves coordinated activities of a number of proteins. The role of plasminogen activator inhibitor-1 (PAI-1) in angiogenesis remains controversial. Utilizing proliferating PAI-1 ؊/؊ endothelial cells (EC), the impact of a host PAI-1 deficiency on Akt activation was evaluated. Hyperactivation of Akt(Ser(P) 473 ) was observed in PAI-1 ؊/؊ EC, and this was probably due to enhanced inactivation of tumor suppressor PTEN, thus rendering the cells resistant to apoptotic signals. Higher levels of inactivated caspase-9 in PAI-1 ؊/؊ EC led to lower levels of procaspase-3 and cleaved caspase-3, thereby promoting survival. These effects were reversed when recombinant PAI-1 was added to PAI-1 ؊/؊ EC. Additional studies demonstrated that regulation of proliferation is dependent on its interaction with low density lipoprotein receptor-related protein. Thus, PAI-1 is a negative regulator of cell growth, exerting its effect on the phosphatidylinositol 3-kinase/Akt pathway and allowing controlled cell proliferation.Angiogenesis is an important biological process involving the formation of new capillaries from preexisting blood vessels, and it occurs in normal as well as pathophysiological settings. It involves a highly orchestrated series of events, including the stimulation of endothelial cells (EC) 2 by growth factors, degradation of the extracellular matrix, migration and proliferation of EC, and formation of new capillary tubes (1, 2). Components of the fibrinolytic pathway have been implicated in the formation of angiogenic vessels, notably plasminogen activators, viz. urokinase-type plasminogen activator (uPA) and tissue-type plasminogen activator. The activation product, plasmin, a trypsin-like serine protease, facilitates degradation of the extracellular matrix, either directly or indirectly through activation of matrix metalloproteases. This process allows migration of EC and subsequent events leading to neovessel formation. However, specific inhibitors control proteolysis of the extracellular matrix, and PAI-1 is an important inhibitor of the plasminogen activation system (3, 4). Considering the important role of the plasminogen activator-PAI-1 system in angiogenesis and the availability of genetically engineered mice lacking various components of this system, several investigators have utilized transgenic approaches to establish the functional potential of components of the plasminogen activator-PAI-1 system in angiogenesis.The role of PAI-1 in angiogenesis and tumor formation has been extensively studied, but results were determined to be dependent on the experimental setting (5-8), the stage of cancer progression, and the origin of the cells (9 -13). It has been demonstrated that implanted malignant keratinocytes were unable to induce vascularization of tumors in PAI-1-deficient mice (PAI-1 Ϫ/Ϫ ) (5). Similarly, T241 fibrosarcoma tumor growth was suppressed in PAI-1 Ϫ/Ϫ mice relative to WT mice (6). In vitro studies demonstrated a lack of microvessel gen...

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Positive correlation between overexpression of phospho-BAD with phosphorylated Akt at serine 473 but not threonine 308 in colorectal carcinoma

Cited by 41 publications

References 34 publications

BAD: undertaker by night, candyman by day

BAD: undertaker by night, candyman by day

Proteomic Analysis of Apoptotic Pathways Reveals Prognostic Factors in Follicular Lymphoma

A Novel Function of Plasminogen Activator Inhibitor-1 in Modulation of the AKT Pathway in Wild-type and Plasminogen Activator Inhibitor-1-deficient Endothelial Cells

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