Role of pRB dephosphorylation in cell cycle regulation

Tamrakar, Sama; Rubin, Ethel; Ludlow, John W.

doi:10.2741/tamrakar

Cited by 92 publications

(80 citation statements)

References 161 publications

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“…As an example, phosphorylated retinoblastoma susceptibility gene pRb is inactive with respect to growth suppression, but dephosphorylated pRb is a very active growth suppressor and regulates cell cycle progression after removal of phosphates (reviewed in ref. 27). Here, we examine the interaction of phosphorylated DCX with spinophilin/neurabin II, a type 1 protein-phosphatase-binding protein (28).…”

Section: Resultsmentioning

confidence: 99%

“…PP1, one of the key eukaryotic serine/threonine protein phosphatases, is involved in the mitotic dephosphorylation of pRb (reviewed in ref. 27), as well as in the dephosphorylation of specific residues of p53 (reviewed in ref. 45), and regulates the control of cell cycle progression (27,45).…”

Section: Discussionmentioning

confidence: 99%

“…27), as well as in the dephosphorylation of specific residues of p53 (reviewed in ref. 45), and regulates the control of cell cycle progression (27,45). PP1 dephosphorylates DCX specifically on amino acid residues S331 and T334 both in vitro and in vivo (31).…”

Section: Discussionmentioning

confidence: 99%

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Ectopic Doublecortin Gene Expression Suppresses the Malignant Phenotype in Glioblastoma Cells

Santra¹,

Zhang²,

Santra³

et al. 2006

Cancer Research

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Doublecortin (DCX) is one of the three genes found from Affymetrix gene chip analysis related to glioma patient survival. Two other genes (e.g., osteonectin and semaphorin 3B) are well characterized as antioncogenic and tumor suppressor genes. However, there is no report about the involvement of DCX in cancer. Here, we show that gene transfer technology into DCX-deficient glioblastoma cell lines, such as A172, U87, U251N, RG2, and 9L, with DCX cDNA significantly suppressed growth of these glioma cells. U87 cells with ectopic expression of DCX exhibit a marked suppression of the transformed phenotype as growth arrested in the G 2 phase of the cell cycle progression, small colony formation in soft agar, and no tumor formation in nude rats. This transformed phenotype can be restored by knocking down DCX expression with DCX small interfering RNA. DCX was highly phosphorylated in glioma cells. Phosphorylation in the glioma cells was greater than in noncancer cells such as mouse NIH 3T3 and human embryonic kidney 293T cells. Coimmunoprecipitation of the phosphorylated DCX and spinophilin/neurabin II from DCX-synthesizing glioma cells indicated their interaction. This interaction would lead to a block of anchorage-independent growth as neurabin II is a synergistic inhibitor of anchorage-independent growth with p14ARF (ARF). Interaction between phosphorylated DCX and neurabin II may induce the association of the protein phosphatase 1 catalytic subunit (PP1) with neurabin II and inactivate PP1 and block mitosis during G 2 and M phases of the cell cycle progression. Thus, DCX seems to be a tumor suppressor of glioma. (Cancer Res 2006; 66(24): 11726-35)

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Ectopic Doublecortin Gene Expression Suppresses the Malignant Phenotype in Glioblastoma Cells

Santra¹,

Zhang²,

Santra³

et al. 2006

Cancer Research

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“…113 All of these findings support the notion that PP2A may function as a tumor-suppressor gene. Although the role of PP1 in tumorigenesis is not as evident as PP2A, it has been reported that PP1 interacts with and dephosphorylates the Rb tumor-suppressor protein returning Rb to its growth suppressive state (reviewed in Tamrakar et al, 2000 114 ), and genetic alterations in PP1 have been identified in human cancers. 115,116 In prostate cancer, especially in advanced prostate cancer, overexpression of cav-1 is frequently observed.…”

Section: Genetic Perturbation and Dysregulation Of The Pi3-k-akt Pathwaymentioning

confidence: 99%

The emerging role of the PI3-K-Akt pathway in prostate cancer progression

Ittmann

Ayala

et al. 2005

Prostate Cancer Prostatic Dis

112

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The PI3-K-Akt pathway plays a central role in the development and progression of prostate cancer and other malignancies. We review original studies and summarize relevant sections of previous reviews concerning the relationships between abnormalities in the PI3-K-Akt pathway and prostate cancer progression. We discuss laboratory and clinical data that indicate gene perturbation and dysregulation of PI3-K-Akt pathway is common in prostate cancer and other malignancies. We further discuss the critical role of the PI3-K-Akt pathway in the oncogenic signaling network and provide examples that establish the PI3-K-Akt pathway as a focal point for the future development of informative biomarkers and effective therapies for prostate cancer.

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“…The first was that the timing of Rb inactivation is critical for cell cycling and survival. Cyclin/cdks phosphorylate and inactivate Rb precisely at mid-to late-G 1 , and then Rb is dephosphorylated and activated again during exit from mitosis (Tamrakar et al, 2000;Classon and Harlow, 2002). Overexpression of E2Fdb, in contrast, effectively inactivates Rb regardless of the cell cycle phase.…”

Section: Binding Of Apoptotic Gene Promoters But Not Cell Cycle Gene mentioning

confidence: 99%