The BAD protein integrates survival signaling by EGFR/MAPK and PI3K/Akt kinase pathways in PTEN-deficient tumor cells

She, Qing‐Bai; Solit, David B.; Ye, Qing; O'Reilly, Kathryn E.; Lobo, Jose; Rosen, Neal

doi:10.1016/j.ccr.2005.09.006

Cited by 375 publications

(364 citation statements)

References 47 publications

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“…21 Taken together, PKB/AKT and DYRK1A have a synergistic result in the translocation of FKHR to the cytoplasm, leading to the suppression of proapoptotic factors, such as Fas ligand, Bim, BAD and Bcl-6. [49][50][51] Our studies also show that DYRK1A alone is able to suppress BAD (Fig. 7) resulting in more cells moving into the proliferative stage.…”

Section: Discussionsupporting

confidence: 65%

Increased expression of Dyrk1a in HPV16 immortalized Keratinocytes enable evasion of apoptosis

Chang

Lin

Yang

et al. 2007

Intl Journal of Cancer

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Immortalization is a critical event in virus-related oncogenesis. No enough information, however, is currently available to elucidate the changes that occur in cellular molecules during immortalization. To identify potential cellular markers or regulators involving in immortalization, a paired-cell model of primary foreskin keratinocytes (FK) and HPV16 immortalized foreskin keratinocytes were established. Using mRNA differential display, RT-PCR and Northern blot methods, we have identified and confirmed that Dyrk1a (dual-specificity tyrosine-phosphorylated and regulated kinase 1A) is present and increased in HPV16 immortalized cells, but is absent in primary keratinocytes. Moreover, transfection of E7 siRNA oligo into immortalized cells leads to a diminishing E7 expression and the eventual disappearance of Dyrk1a. Similar results of Dyrk1a expressional differences could also be seen when tissue specimens were compared using LCM/real-time PCR and immunohistochemistry analysis; malignant cervical lesions contain significantly more DYRK1A than normal tissue. It was also demonstrated that raised DYRK1A could rearrange the cellular localization of FKHR (forkhead in rhabdomyosarcoma), an apoptosis activator, and suppress BAD. Importantly, this phenomenon can be reversed when endogenous Dyrk1a was knocked down in immortalized cells by RNA interference. These results suggest that the raised Dyrk1a in HPV16 immortalized keratinocytes and cervical lesions may serve as a candidate antiapoptotic factor in the FKHR regulated pathway and initiate immortalization and tumorigenesis gradually. ' 2007 Wiley-Liss, Inc.Key words: HPV16; keratinocytes; Dyrk1a; immortalization; apoptosis Mammalian cells have a limited life span and proliferating capacity when cultivated in vitro. Replicate senescence or the terminal arrest state, has been found to be accompanied by several molecular changes that lead to an activated suppression of the cell cycle and the shortening of the telomeres. 1 Similar to apoptosis, cellular senescence is thought to be a mechanism of tumor suppression because it prevents the outgrowth of cells that have acquired mutations in genes rendering them cancerous. Consistent with this model, several tumor suppressor genes (such as, overexpressed p16 or ZNF217, activated p53 and deregulated Rassf1a or c-myc, etc) or their products have been reported and shown to be associated in parallel with telomere irregularities at the onset of cellular senescence. 2 Telomere shortening has been shown to generate unstable DNA leading to p53 activation and the subsequent transcriptional induction of the cdk inhibitor p21 CIP13 that moves cells into senescence state. Therefore, preventing telomere erosion by ectopic expression of telomerase is sufficient to immortalized primary cells in vitro and thus extend life span. [4][5][6] Although it works in human fibroblast, telemorase alone, however, is not sufficient to induce immortalization in human keratinocytes and mammary epithelial cells. 7 To identify other factors that are involved ...

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Section: Discussionsupporting

confidence: 65%

Increased expression of Dyrk1a in HPV16 immortalized Keratinocytes enable evasion of apoptosis

Chang

Lin

Yang

et al. 2007

Intl Journal of Cancer

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“…Consistently, Pim-3 transgenic mice exhibited enhanced phosphorylation of Bad at Ser 112 in the liver. The proapoptotic activity of Bad is regulated by its phosphorylation at (She et al, 2005). Unphosphorylated Bad binds and eventually inactivates anti-apoptotic family members, primarily Bcl-X L and even Bcl-2 (Yang et al, 1995;Zha et al, 1996).…”

Section: Discussionmentioning

confidence: 99%

Accelerated hepatocellular carcinoma development in mice expressing the Pim-3 transgene selectively in the liver

Wang

Nakamoto

et al. 2010

Oncogene

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Pim-3, a proto-oncogene with serine/threonine kinase activity, was enhanced in hepatocellular carcinoma (HCC) tissues. To address the roles of Pim-3 in HCC development, we prepared transgenic mice that express human Pim-3 selectively in liver. The mice were born at a Mendelian ratio, were fertile and did not exhibit any apparent pathological changes in the liver until 1 year after birth. Pim-3-transgenic mouse-derived hepatocytes exhibited accelerated cell cycle progression. The administration of a potent hepatocarcinogen, diethylnitrosamine (DEN), induced accelerated proliferation of liver cells in Pim-3 transgenic mice in the early phase, compared with that observed for wild-type mice. Treatment with DEN induced lipid droplet accumulation with increased proliferating cell numbers 6 months after the treatment. Eventually, wild-type mice developed HCC with a frequency of 40% until 10 month after the treatment. Lipid accumulation was accelerated in Pim-3 transgenic mice with higher proliferating cell numbers, compared with that observed for wild-type mice. Pim-3 transgenic mice developed HCC with a higher incidence (80%) and a heavier burden, together with enhanced intratumoral CD31-positive vascular areas, compared with that observed for wild-type mice. These observations indicate that Pim-3 alone cannot cause, but can accelerate HCC development when induced by a hepatocarcinogen, such as DEN.

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“…205 When Bad associates with Bcl-2 or Bcl-X L , it promotes apoptosis by preventing Bcl-2 or Bcl-X L from interacting with Bax. [206][207][208][209][210][211][212] Bad is phosphorylated in most AML specimens suggesting that inhibition of Bad phosphorylation may be therapeutically important in AML. 213 In contrast, the antiapoptotic Mcl-1 protein is not reported to interact with Bad.…”

Section: Overview Of Jak/stat Pathwaymentioning

confidence: 99%

Contributions of the Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways to leukemia

et al. 2008

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Mutations and chromosomal translocations occur in leukemic cells that result in elevated expression or constitutive activation of various growth factor receptors and downstream kinases. The Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways are often activated by mutations in upstream genes. The Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR pathways are regulated by upstream Ras that is frequently mutated in human cancer. Recently, it has been observed that the FLT-3 and Jak kinases and the phosphatase and tensin homologue deleted on chromosome 10 ( PTEN) phosphatase are also frequently mutated or their expression is altered in certain hematopoietic neoplasms. Many of the events elicited by the Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways have direct effects on survival pathways. Aberrant regulation of the survival pathways can contribute to uncontrolled cell growth and lead to leukemia. In this review, we describe the Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT signaling cascades and summarize recent data regarding the regulation and mutation status of these pathways and their involvement in leukemia

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The BAD protein integrates survival signaling by EGFR/MAPK and PI3K/Akt kinase pathways in PTEN-deficient tumor cells

Cited by 375 publications

References 47 publications

Increased expression of Dyrk1a in HPV16 immortalized Keratinocytes enable evasion of apoptosis

Increased expression of Dyrk1a in HPV16 immortalized Keratinocytes enable evasion of apoptosis

Accelerated hepatocellular carcinoma development in mice expressing the Pim-3 transgene selectively in the liver

Contributions of the Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways to leukemia

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