Loss of Smad3 in Acute T-Cell Lymphoblastic Leukemia

Wolfraim, Lawrence A.; Fernández, Tania Miñes; Mamura, Mizuko; Fuller, Walter; Kumar, Rajesh; Cole, Diane E.; Byfield, Stacey DaCosta; Felici, Angelina; Flanders, Kathleen C.; Walz, Thomas; Roberts, Anita B.; Aplan, Peter D.; Balis, Frank M.; Letterio, John J.

doi:10.1056/nejmoa031197

Cited by 153 publications

(108 citation statements)

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“…56 Although there have been no mutations reported thus far in the Smad3 gene isolated from tumors, recent studies have provided direct evidence that Smad3 is an important tumor suppressor in pediatric T-cell acute lymphoblastic leukemia (ALL) and gastric cancer. 57,58 Whereas Smad3 mRNA is present at normal levels, Smad3 protein is absent in leukemic cells from children with T cell ALL. 57 Loss of Smad3 protein is a specific feature of pediatric T-cell ALL, but not pre-B-cell ALL.…”

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confidence: 99%

“…57,58 Whereas Smad3 mRNA is present at normal levels, Smad3 protein is absent in leukemic cells from children with T cell ALL. 57 Loss of Smad3 protein is a specific feature of pediatric T-cell ALL, but not pre-B-cell ALL. 57 In a mouse model, reduced Smad3 level (Smad3 +/-) and the loss of CDK inhibitor p27 (p27 -/-) synergistically promote T-cell leukemogenesis.…”

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confidence: 99%

“…57 Loss of Smad3 protein is a specific feature of pediatric T-cell ALL, but not pre-B-cell ALL. 57 In a mouse model, reduced Smad3 level (Smad3 +/-) and the loss of CDK inhibitor p27 (p27 -/-) synergistically promote T-cell leukemogenesis. 57 For gastric cancers, three out of eight gastric cancer patients analyzed had no Smad3 protein detectable in the gastric cancer tissues.…”

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confidence: 99%

“…57 In a mouse model, reduced Smad3 level (Smad3 +/-) and the loss of CDK inhibitor p27 (p27 -/-) synergistically promote T-cell leukemogenesis. 57 For gastric cancers, three out of eight gastric cancer patients analyzed had no Smad3 protein detectable in the gastric cancer tissues. 58 In addition, two out of nine gastric cancer cell lines are deficient in Smad3 protein level, with concomitant low mRNA levels.…”

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confidence: 99%

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Inhibition of Smad Antiproliferative Function by CDK Phosphorylation

Liu¹,

Matsuura²

2004

Cell Cycle

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Rb family members were the only demonstrated substrates of CDK4 until it was shown recently that Smad3, which plays a key role in mediating TGF-β antiproliferative responses, is phosphorylated by both CDK4 and CDK2 in vivo and in vitro. CDK phosphorylation of Smad3 inhibits its transcriptional activity and antiproliferative function. The Rb pathway is disrupted in almost all human cancers. Most cancers contain high levels of CDK activity due to frequent inactivation of the p16 tumor suppressor or overexpression of cyclin D1. Therefore, disruption of the Rb pathway not only inactivates Rb, but also likely diminishes Smad activity, which may contribute to tumorigenesis and resistance to the TGF-β growth-inhibitory effects in cancers. Although genetic mutation of Smad3 has not been reported, CDK phosphorylation of Smad3 may provide an epigenetic mechanism for inhibition of the tumor suppressive function of Smad3 during the early stages of tumorigenesis.Cell cycle control is closely associated with cancer. 1-3 Periodic expression of various cyclins activates different cyclin-dependent kinases (CDKs) at specific stages of the cell cycle. 4 The CDKs that function during the first gap phase (G 1 ) include the homologous CDK4 and CDK6 as well as CDK2. 4 CDK4 and CDK6 are complexed with D type cyclins in early-mid G 1 phase. CDK2 is complexed with E-and A-type cyclins during late G 1 and S phase, respectively. G 1 CDKs are negatively controlled by two classes of CDK inhibitors. 4 The first class includes four members of the INK4 family (p16, p15, p18 and p19), which specifically inhibit CDK4 and CDK6 activities. 4 The second class consists of three members of the Cip/Kip family (p21, p27, and p57), which inhibit cyclin E or cyclin A associated CDK2 activity, and at high doses, also inhibit cyclin D-CDK4/6 activities. 4 Both CDK4/6 and CDK2 target the Rb tumor suppressor. [1][2][3][4][5] In the hypophosphorylated state, Rb binds to and inhibits E2F activity. 3-6 G 1 CDK phosphorylation of Rb leads to the release of free active E2F, which can then activate the transcription of a number of genes that are essential for G 1 /S transition. [3][4][5][6] In addition to Rb, several other proteins, including certain components of the cell cycle machinery, can be phosphorylated by CDK2. 4 In contrast, the Rb family members have been the only demonstrated substrates for CDK4 for the past eleven years. Our recent study indicates that Smad3, a key mediator for TGF-β antiproliferative responses, is a target for inhibitory phosphorylation by both CDK4 and CDK2, revealing a distinct regulation in the complex cell cycle regulatory network. 7 TGF-β potently inhibits cell proliferation by causing cell cycle arrest at the G 1 phase and is an important tumor suppressor during the early stages of tumorigenesis. 8,9 TGF-β signals through the type I and type II transmembrane serine/threonine kinase receptors. [8][9][10][11] It binds and brings together the type I and type II receptors. In the resulting complex, the constitutively active ...

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confidence: 99%

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confidence: 99%

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confidence: 99%

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confidence: 99%

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Inhibition of Smad Antiproliferative Function by CDK Phosphorylation

Liu¹,

Matsuura²

2004

Cell Cycle

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“…However, since T-ALL represents the rare subtype of paediatric ALL most studies have to be performed in small groups of patients as recently shown. 12 In summary, we investigated in an exploratory study TRF, TA and expression of hTERT in leukaemic cells of paediatric patients with T-ALL and could not observe significant relationships between these biological parameters and clinical outcome or prognosis. Further controlled long-term studies with larger populations are probably needed to elucidate the clinical value of these biochemical markers for monitoring the course of paediatric T-ALL.…”

Section: Telomeres and Telomerase In Paediatric Patients With T-cell mentioning

confidence: 86%