A Novel Role of p38&amp;alpha; MAPK in Mitotic Progression Independent of Its Kinase Activity

Fan, Li; Yang, Xianlin; Du, Jian; Marshall, Mark S.; Blanchard, Kerry; Xiang, Yu‐Tao

doi:10.4161/cc.4.11.2125

Cited by 30 publications

(33 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In earlier studies, the active form of p38 MAPK was found in the cytosol of mitotic cells (Fan et al, 2005) or localized to the mitotic spindle poles (Tang et al, 2008). Here, we extend these findings by reporting kinetochore signals after immunofluorescent detection with an antibody recognizing the conserved Thr180,Tyr182 phosphoepitope present in all p38 MAPK isoforms.…”

Section: Control Of P38 Mapk Activity During Mitosissupporting

confidence: 65%

Loss of p38γ MAPK induces pleiotropic mitotic defects and massive cell death

Kukkonen-Macchi

Sicora

Kaczyńska

et al. 2011

Journal of Cell Science

View full text Add to dashboard Cite

SummaryThe p38 mitogen-activated protein kinase (p38 MAPK) family, which is comprised of four protein isoforms, p38, p38, p38 and p38, forms one of the key MAPK pathways. The p38 MAPKs are implicated in many cellular processes including inflammation, differentiation, cell growth, cell cycle and cell death. The function of p38 MAPKs in mitotic entry has been well established, but their role in mitotic progression has remained controversial. We identify p38 MAPK as a modulator of mitotic progression and mitotic cell death. In HeLa cells, loss of p38 results in multipolar spindle formation and chromosome misalignment, which induce a transient M phase arrest. The majority of p38-depleted cells die at mitotic arrest or soon after abnormal exit from M-phase. We show that p38 MAPKs are activated at the kinetochores and spindle poles throughout mitosis by kinase(s) that are stably bound to these structures. Finally, p38 is required for the normal kinetochore localization of polo-like kinase 1 (Plk1), and this contributes to the activity of the p38 MAPK pathway. Our data suggest a link between mitotic regulation and the p38 MAPK pathway, in which p38 prevents chromosomal instability and supports mitotic cell viability.

show abstract

Section: Control Of P38 Mapk Activity During Mitosissupporting

confidence: 65%

Loss of p38γ MAPK induces pleiotropic mitotic defects and massive cell death

Kukkonen-Macchi

Sicora

Kaczyńska

et al. 2011

Journal of Cell Science

View full text Add to dashboard Cite

show abstract

“…The use of biochemical inhibitors and chemical genotoxic compounds in this study was performed as previously described (11,46). Chemical inhibitors used in this study were synthesized by Lilly chemists.…”

Section: Methodsmentioning

confidence: 99%

“…Protein lysates of cultured cells were prepared in a lysate buffer containing a cocktail of phosphatase and protease inhibitors, and Western blotting was performed as previously described (11). Luminescent substrate detection was performed by using the ECL Advance or ECL Plus chemiluminescent kit (Amersham, Piscataway, NJ).…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

p38 Mitogen-Activated Protein Kinase Promotes Cell Survival in Response to DNA Damage but Is Not Required for the G₂ DNA Damage Checkpoint in Human Cancer Cells

Phong

Horn

et al. 2010

Molecular and Cellular Biology

View full text Add to dashboard Cite

p38 mitogen-activated protein kinase (MAPK) is rapidly activated by stresses and is believed to play an important role in the stress response. While Chk1 is known to mediate G 2 DNA damage checkpoint control, p38 was also reported to have an essential function in this checkpoint control. Here, we have investigated further the roles of p38 and Chk1 in the G 2 DNA damage checkpoint in cancer cells. We find that although p38 activation is strongly induced by DNA damage, its activity is not required for the G 2 DNA damage checkpoint. In contrast, Chk1 kinase is responsible for the execution of G 2 DNA damage checkpoint control in p53-deficient cells. The inhibition of p38 activity has no effect on Chk1 activation and ␥-H2AX expression. Global gene expression profiling of cancer cells in response to tumor necrosis factor alpha (TNF-␣) revealed that p38 plays a strong prosurvival role through the coordinated downregulation of proapoptotic genes and upregulation of prosurvival genes. We show that the inhibition of p38 activity during G 2 DNA damage checkpoint arrest triggers apoptosis in a p53-independent manner with a concurrent decrease in the level of Bcl2 family proteins. Our results suggest that although p38 MAPK is not required for the G 2 DNA damage checkpoint function, it plays an important prosurvival role during the G 2 DNA damage checkpoint response through the upregulation of the Bcl2 family proteins.

show abstract

“…The cell cycle arrest in G 2 -M phase suggested a possible role of activated p38 MAPK in SNARE-1 antagonism (28)(29)(30). In addition, phosphorylation of p38 MAPK has been implicated in antiproliferative and proapoptotic effects (31).…”

Section: Resultsmentioning

confidence: 99%

Discovery and Mechanistic Characterization of a Novel Selective Nuclear Androgen Receptor Exporter for the Treatment of Prostate Cancer

et al. 2010

View full text Add to dashboard Cite

Despite the success of medical strategies to reduce androgen levels in the treatment of prostate cancer, this disease invariably relapses to a castrate-resistant state that is generally fatal. Although it had been thought that androgen-insensitive cancers no longer relied on the androgen receptor (AR) for growth and survival, it is now clear that this is not the case. Because relapses are known to occur by many mechanisms that keep the AR functionally active, strategies to block AR accumulation in the nucleus may be therapeutically useful. Here, we report the discovery of a selective nuclear androgen receptor exporter (SNARE) that functions to exclude AR from the nucleus. SNARE-1 binds wild-type and mutant ARs and efficiently inhibits their transactivation activity and ability to induce PSA gene expression. SNARE-1 inhibits the androgen-sensitive growth of LNCaP cells and tumor xenografts. Quantitative subcellular localization studies suggest that SNARE-1 inhibits nuclear translocation of AR, but also facilitates export of nuclear AR that has been translocated by an agonist. Mechanistic studies indicate that SNARE-1 rapidly phosphorylates p38 mitogen-activated protein kinase (MAPK) and Ser 650 of the AR. Additionally, SNARE-1 was found to promote ubiquitination of AR in LNCaP cells. Lastly, SNARE-1 functions as a tissue-selective AR inhibitor, as it fails to phosphorylate p38 MAPK in U2OS bone cells that are stably transfected with AR. In summary, SNARE-1 inhibits AR function by a mechanism that is distinct from clinically available antiandrogens, such that it might inform novel methods to block AR function in androgen-independent prostate cancer. Cancer Res; 70(2); 842-51. ©2010 AACR.

show abstract

A Novel Role of p38α MAPK in Mitotic Progression Independent of Its Kinase Activity

Cited by 30 publications

References 37 publications

Loss of p38γ MAPK induces pleiotropic mitotic defects and massive cell death

Loss of p38γ MAPK induces pleiotropic mitotic defects and massive cell death

p38 Mitogen-Activated Protein Kinase Promotes Cell Survival in Response to DNA Damage but Is Not Required for the G₂ DNA Damage Checkpoint in Human Cancer Cells

Discovery and Mechanistic Characterization of a Novel Selective Nuclear Androgen Receptor Exporter for the Treatment of Prostate Cancer

Contact Info

Product

Resources

About

A Novel Role of p38&alpha; MAPK in Mitotic Progression Independent of Its Kinase Activity

Cited by 30 publications

References 37 publications

Loss of p38γ MAPK induces pleiotropic mitotic defects and massive cell death

Loss of p38γ MAPK induces pleiotropic mitotic defects and massive cell death

p38 Mitogen-Activated Protein Kinase Promotes Cell Survival in Response to DNA Damage but Is Not Required for the G2 DNA Damage Checkpoint in Human Cancer Cells

Discovery and Mechanistic Characterization of a Novel Selective Nuclear Androgen Receptor Exporter for the Treatment of Prostate Cancer

Contact Info

Product

Resources

About

A Novel Role of p38α MAPK in Mitotic Progression Independent of Its Kinase Activity

p38 Mitogen-Activated Protein Kinase Promotes Cell Survival in Response to DNA Damage but Is Not Required for the G₂ DNA Damage Checkpoint in Human Cancer Cells