The p57 CDKi integrates stress signals into cell-cycle progression to promote cell survival upon stress

Joaquin, Manel; Gubern, Albert; González-Nuñez, Daniel; Ruiz, E. Josué; Ferreiro, Isabel; Nadal, Eulàlia de; Nebreda, Ángel R.; Posas, Francesc

doi:10.1038/emboj.2012.122

Cited by 53 publications

(57 citation statements)

References 53 publications

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“…This is consistent with a recent study that p57Kip2 can also be phosphorylated by p38MAPK under osmostress or ultraviolet, and this phosphorylation per se seems to promote cell survival as well 56 but is in contrast to other studies showing that p57Kip2 has anti-survival effects. 57,58 Further investigation is needed to understand how p57Kip2 executes distinct functions under these conditions.…”

Section: Discussionsupporting

confidence: 93%

p57Kip2 is an unrecognized DNA damage response effector molecule that functions in tumor suppression and chemoresistance

et al. 2014

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The DNA damage response (DDR) helps to maintain genome integrity, suppress tumorigenesis and mediate the radiotherapeutic and chemotherapeutic effects on cancer. Here we report that p57Kip2, a cyclin-dependent kinase (CDK) inhibitor implicated in the development of tumor-prone Beckwith-Wiedemann syndrome, is an effector molecule of the DNA-damage response. Genotoxic stress induces p57Kip2 expression via the bone morphogenetic protein-Smad1 and Atm-p38MAPK-Atf2 pathways in p53-proficient or -deficient cells and requires the Smad1-Atf2 complex that facilitates their recruitment to the p57Kip2 promoter. Elevated p57Kip2 induces G1/S phase cell cycle arrest but inhibits cell death in response to DNA damage and acts in parallel with p53 to suppress cell transformation and tumor formation. p57Kip2 is also upregulated in stage I and II clinical rectal tumor samples, likely due to genome instability of precancerous and/or early cancer cells. Targeting p57Kip2 in primary rectal cancer cells and tumor models resulted in increased sensitivity to doxorubicin, suggesting that p57Kip2 has a role in chemoresistance, which is consistent with its pro-survival function. These findings place p57Kip2 in DDR and uncover molecular mechanisms by which p57Kip2 suppresses tumorigenesis and causes chemoresistance.

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Section: Discussionsupporting

confidence: 93%

p57Kip2 is an unrecognized DNA damage response effector molecule that functions in tumor suppression and chemoresistance

et al. 2014

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“…Recently, it has been reported that p57 Kip2 integrates stress signals into cell cycle progression to promote cell survival upon stress (Joaquin et al, 2012). The stability of the p57…”

Section: Pak4 Suppresses P57mentioning

confidence: 99%

P21‐Activated Kinase 4 Regulates the Cyclin‐Dependent Kinase Inhibitor P57^Kip2 in Human Breast Cancer

Wang

Zhang

et al. 2013

The Anatomical Record

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The p21-activated kinases have been implicated in the control of cell cycle progression. However, the biological mechanism underlying the role of p21-activated kinase 4 (PAK4) in cell cycle control remains unknown. Here, by using quantitative RT-PCR and immunoblot analyses, we discovered that over-expression of PAK4 could suppress cyclin-dependent kinase inhibitor 1C ( p57 Kip2 ) expression in the MCF-7 human breast cancer cell line, whereas lentiviral vector-mediated small interfering RNA (siRNA) knockdown of PAK4 markedly promoted p57Kip2 expression in MCF-7 cells. Furthermore, PAK4-mediated down-regulation of p57Kip2 was reversed by MG132, a specific proteasome inhibitor. The ubiquitination assay confirmed that the activity of PAK4 attenuated p57Kip2 protein stability through the ubiquitin-proteasome pathway in MCF-7 cells. Moreover, a significant inverse correlation between PAK4 and p57Kip2 protein levels was observed in breast cancer tissues by immunohistochemical analysis. Taken together, our data demonstrate a novel function for PAK4 in regulating the stability of p57 Kip2, possibly through the ubiquitin-proteasome pathway, leading to increased proliferation of breast cancer cells. Thus, PAK4 may be used as a potential diagnostic and therapeutic target for human breast cancer. Anat Rec, 296:1561Rec, 296: -1567Rec, 296: , 2013. V C 2013 Wiley Periodicals, Inc.

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“…Mammalian cell cycle progression throughout the G 1 phase is controlled by signaling pathways that regulate the activities of G 1 CDK4/6-cyclin D and CDK2-cyclin E/A, which are responsible for modulating the expression, activity, and stability of many cell cycle regulatory proteins, particularly in spe-cialized cells, including the hematopoietic lineage (15,16). According to the classical model of cell cycle control, CDK4 or CDK6 regulates events in the early G 0 to G 1 phase, CDK2 triggers the S phase, CDK2/CDK1 regulate the completion of the S phase, and CDK1 is responsible for mitosis.…”

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confidence: 99%

Cell Cycle Control and HIV-1 Susceptibility Are Linked by CDK6-Dependent CDK2 Phosphorylation of SAMHD1 in Myeloid and Lymphoid Cells

Pauls

Ruiz

Badía

et al. 2014

The Journal of Immunology

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118

135

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Proliferating cells are preferentially susceptible to infection by retroviruses. Sterile α motif and HD domain–containing protein-1 (SAMHD1) is a recently described deoxynucleotide phosphohydrolase controlling the size of the intracellular deoxynucleotide triphosphate (dNTP) pool, a limiting factor for retroviral reverse transcription in noncycling cells. Proliferating (Ki67+) primary CD4+ T cells or macrophages express a phosphorylated form of SAMHD1 that corresponds with susceptibility to infection in cell culture. We identified cyclin-dependent kinase (CDK) 6 as an upstream regulator of CDK2 controlling SAMHD1 phosphorylation in primary T cells and macrophages susceptible to infection by HIV-1. In turn, CDK2 was strongly linked to cell cycle progression and coordinated SAMHD1 phosphorylation and inactivation. CDK inhibitors specifically blocked HIV-1 infection at the reverse transcription step in a SAMHD1-dependent manner, reducing the intracellular dNTP pool. Our findings identify a direct relationship between control of the cell cycle by CDK6 and SAMHD1 activity, which is important for replication of lentiviruses, as well as other viruses whose replication may be regulated by intracellular dNTP availability.

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The p57 CDKi integrates stress signals into cell-cycle progression to promote cell survival upon stress

Abstract: The p57 CDKi integrates stress signals into cell-cycle progression to promote cell survival upon stressThe stress-activated protein kinase p38 phosphorylates p57/Kip2, resulting in enhanced CDK2 inhibition and a cell-cycle delay that helps cells to survive under stress.

Cited by 53 publications

References 53 publications

p57Kip2 is an unrecognized DNA damage response effector molecule that functions in tumor suppression and chemoresistance

p57Kip2 is an unrecognized DNA damage response effector molecule that functions in tumor suppression and chemoresistance

P21‐Activated Kinase 4 Regulates the Cyclin‐Dependent Kinase Inhibitor P57^Kip2 in Human Breast Cancer

Cell Cycle Control and HIV-1 Susceptibility Are Linked by CDK6-Dependent CDK2 Phosphorylation of SAMHD1 in Myeloid and Lymphoid Cells

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The p57 CDKi integrates stress signals into cell-cycle progression to promote cell survival upon stress

Abstract: The p57 CDKi integrates stress signals into cell-cycle progression to promote cell survival upon stressThe stress-activated protein kinase p38 phosphorylates p57/Kip2, resulting in enhanced CDK2 inhibition and a cell-cycle delay that helps cells to survive under stress.

Cited by 53 publications

References 53 publications

p57Kip2 is an unrecognized DNA damage response effector molecule that functions in tumor suppression and chemoresistance

p57Kip2 is an unrecognized DNA damage response effector molecule that functions in tumor suppression and chemoresistance

P21‐Activated Kinase 4 Regulates the Cyclin‐Dependent Kinase Inhibitor P57Kip2 in Human Breast Cancer

Cell Cycle Control and HIV-1 Susceptibility Are Linked by CDK6-Dependent CDK2 Phosphorylation of SAMHD1 in Myeloid and Lymphoid Cells

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About

P21‐Activated Kinase 4 Regulates the Cyclin‐Dependent Kinase Inhibitor P57^Kip2 in Human Breast Cancer