MAPK14
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesMAPK14, CSBP, CSBP1, CSBP2, CSPB1, EXIP, Mxi2, PRKM14, PRKM15, RK, SAPK2A, p38, p38ALPHA, mitogen-activated protein kinase 14
External IDsOMIM: 600289 MGI: 1346865 HomoloGene: 31777 GeneCards: MAPK14
Orthologs
SpeciesHumanMouse
Entrez

1432

26416

Ensembl

ENSG00000112062

ENSMUSG00000053436

UniProt

Q16539

P47811

RefSeq (mRNA)

NM_001315
NM_139012
NM_139013
NM_139014

NM_001168508
NM_001168513
NM_001168514
NM_011951
NM_001357724

RefSeq (protein)

NP_001306
NP_620581
NP_620582
NP_620583

NP_001161980
NP_001161985
NP_001161986
NP_036081
NP_001344653

Location (UCSC)Chr 6: 36.03 – 36.11 MbChr 17: 28.91 – 28.97 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Mitogen-activated protein kinase 14, also called p38-α, is an enzyme that in humans is encoded by the MAPK14 gene.[5]

MAPK14 encodes p38α mitogen-activated protein kinase (MAPK) which is the prototypic member of the p38 MAPK family. p38 MAPKs are also known as stress-activated serine/threonine-specific kinases (SAPKs). In addition to MAPK14 for p38α MAPK, the p38 MAPK family has three additional members, including MAPK11, MAPK12 and MAPK13 which encodes p38β MAPK, p38γ MAPK and p38δ MAPK isoforms, respectively. p38α MAPK was originally identified as a tyrosine phosphorylated protein detected in activated immune cell macrophages with an essential role in inflammatory cytokine induction, such as Tumor Necrotic Factor α (TNFα).[6][7] However, p38α MAPK mediated kinase activity has been implicated in many tissues beyond immune systems. p38α MAPK is mainly activated through MAPK kinase kinase cascades and exerts its biological function via downstream substrate phosphorylation. p38α MAPK is implicated in diverse cellular functions, from gene expression to programmed cell death through a network of signaling molecules and transcription factors. Pharmacological and genetic inhibition of p38α MAPK not only revealed its biological significance in physiological function but also the potential of targeting p38α MAPK in human disease such as immune disorders and heart failure.

Structure

MAPK14 is a 41 kDa protein composed of 360 amino acids.[8][9]

Function

The protein encoded by this gene is a member of the MAP kinase family. MAP kinases act as an integration point for multiple biochemical signals, and are involved in a wide variety of cellular processes such as proliferation, differentiation, transcription regulation and development. This kinase is activated by various environmental stresses and proinflammatory cytokines. The activation requires its phosphorylation by MAP kinase kinases (MKKs), or its autophosphorylation triggered by the interaction of MAP3K7IP1/TAB1 protein with this kinase. The substrates of this kinase include transcription regulator ATF2, MEF2C, and MAX, cell cycle regulator CDC25B, and tumor suppressor p53, which suggest the roles of this kinase in stress-related transcription and cell cycle regulation, as well as in genotoxic stress response. Four alternatively spliced transcript variants of this gene encoding distinct isoforms have been reported.[10]

p38α MAPK is ubiquitously expressed in many cell types, in contrast, p38β MAPK is highly expressed in brain and lung, p38γ MAPK mostly in skeletal muscle and nerve system, and p38δ MAPK in uterus and pancreas.[11][12] Like all MAP kinases, p38α MAPK has 11 conserved domains (Domains I to XI) and a Thr-Gly-Tyr (TGY) dual phosphorylation motif. Activation of p38 MAPK pathway has been implicated in a variety of stress response in addition to inflammation, including osmotic shock, heat, and oxidative stress.[11][13][14] The canonical pathway for p38 MAPK activation involve a cascade of protein kinases, including MAP3K such as MEKK1, 2, 3 and 4, TGFβ-activated kinase (TAK1), TAO1-3, mixed-lineage kinase 2/3 (MLK2/3), and apoptosis signal-regulating kinase 1/2 (ASK1/2), as well as MAP2Ks, such as MKK3, 6 and 4. MAP2K mediated phosphorylation of the TGY motif results in conformational change of p38 MAPK which allows kinase activation and accessibility to substrates.[15] In addition, TAK1-binding protein 1 (TAB1) and ZAP70 can induce p38 MAPK via non-canonical autophosphorylation.[16][17][18] Furthermore, acetylation of p38 MAPK at lys-53 of the ATP-binding pocket also enhances p38 MAPK activity during cellular stress[19] Under basal conditions, p38α MAPK is detected in both the nucleus and the cytoplasm. One of the consequences of p38 MAPK activation is translocation into the nucleus.[20] involving both p38 MAPK phosphorylation and microtubule- and dynein-dependent process.[21] In addition, one substrate of p38 MAPK, MAP kinase-activated protein kinase 2 (MAPAK2 or MK2) can modulate and direct p38α MAPK localization to cytosole via direct interaction.[22] p38α MAPK activation can be reversed by dephosphorylation of the TGY motif carried out by protein phosphatases, including ser-thr protein phosphatases (PPs), protein tyrosine phosphatases (PTP), and dual-specificity phosphatases (DUSP). For example, ser/thr phosphatases PP2Cα/β suppress activity of p38s MAPK through direct interaction as well as suppression of MKKs/TAK1 in mammalian cells.[23][24] Hematopoietic PTP (HePTP) and striatal-enriched phosphatase (STEP) bind to MAPKs through a kinase-interaction motif (KIM) and inactivates them by dephosphorylating the phosphotyrosine residue in their activation loop.[25][26][27] DUSPs, which have a docking domain to MAPKs and dual-specific phosphatase activity, can also bind to p38 MAPKs and dephosphorylate of both phosphotyrosine and phosphothreonine residues.[15] In addition to these phosphatases, other molecular components such as Hsp90-Cdc37 chaperone complex can also modulate p38 MAPK autophosphorylation activity and prevents non-canonical activation.[28]

p38α MAPK is implicated in cell survival/apoptosis, proliferation, differentiation, migration, mRNA stability, and inflammatory response in different cell types through variety of different target molecules[29] MK2 is one of the well-studied downstream targets of p38α MAPK. Their downstream substrates include small heat shock protein 27 (HSP27), lymphocyte-specific protein1 (LSP1), cAMP response element-binding protein (CREB), cyclooxygenase 2 (COX2), activating transcription factor 1 (ATF1), serum response factor (SRF), and mRNA-binding protein tristetraprolin (TTP)[20][30] In addition to protein kinases, many transcription factors are downstream targets of p38α MAPK, including ATF1/2/6, c-Myc, c-FOS, GATA4, MEF2A/C, SRF, STAT1, and CHOP[31][32][33][34]

Role in cardiovascular system

p38α MAPK constitutes the main p38 MAPK activity in heart. During cardiomyocyte maturation in new born mouse heart, p38α MAPK activity can regulate myocyte cytokinesis and promote cell cycle exit.[35] while inhibition of p38 MAPK activity leads to induction of mitosis in both adult and fetal cardiomyocyte.[36][37] Therefore, p38 MAPK is associated with cell-cycle arrest in mammalian cardiomyocytes and its inhibition may represent a strategy to promote cardiac regeneration in response to injury. In addition, p38α MAPK induction promotes myocyte apoptosis.[38][39] via downstream targets STAT1, CHOP, FAK, SMAD, cytochrome c, NF-κB, PTEN, and p53.[40][41][42][43][44][45][46] p38 MAPK can also target IRS-1 mediated AKT signaling and promotes myocyte death under chronic insulin stimulation.[47] Inhibition of p38 MAPK activity confers cardioprotection against ischemia reperfusion injury in heart[48][49] However, some reports demonstrated that p38 MAPK also involves in anti-apoptotic effect via phosphorylation of αβ-Crystallin or induction of Pim-3 during early response to oxidative stress or anoxic preconditioning respectively[50][51][52] Both p38α MAPK and p38β MAPK appear to have an opposite role in apoptosis.[53] Whereas p38α MAPK has a pro-apoptotic role via p53 activation, p38β MAPK has a pro-survival role via inhibition of ROS formation.[54][55] In general, chronic activation of p38 MAPK activity is viewed as pathological and pro-apoptotic, and inhibition of p38 MAPK activity is in clinical evaluation as a potential therapy to mitigate acute injury in ischemic heart failure.[56] p38 MAPK activity is also implicated in cardiac hypertrophy which is a significant feature of pathological remodeling in the diseased hearts and a major risk factor for heart failure and advert outcome. Most in vitro evidence supports that p38 MAPK activation promotes cardiomyocyte hypertrophy.[53][57][58][59] However, in vivo evidence suggest that chronic activation of p38 MAPK activity triggers restrictive cardiomyopathy with limited hypertrophy,[60] while genetic inactivation p38α MAPK in mouse heart results in an elevated cardiac hypertrophy in response to pressure overload[61][62] or swimming exercise.[63] Therefore, the functional role of p38 MAPK in cardiac hypertrophy remains controversial and yet to be further elucidated.

Interactions

MAPK14 has been shown to interact with:

Notes

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000112062 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000053436 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ Lee JC, Laydon JT, McDonnell PC, Gallagher TF, Kumar S, Green D, McNulty D, Blumenthal MJ, Heys JR, Landvatter SW (January 1995). "A protein kinase involved in the regulation of inflammatory cytokine biosynthesis". Nature. 372 (6508): 739–46. doi:10.1038/372739a0. PMID 7997261. S2CID 4306822.
  6. ↑ Han J, Lee JD, Bibbs L, Ulevitch RJ (Aug 1994). "A MAP kinase targeted by endotoxin and hyperosmolarity in mammalian cells". Science. 265 (5173): 808–11. Bibcode:1994Sci...265..808H. doi:10.1126/science.7914033. PMID 7914033.
  7. ↑ Han J, Lee JD, Tobias PS, Ulevitch RJ (Nov 1993). "Endotoxin induces rapid protein tyrosine phosphorylation in 70Z/3 cells expressing CD14". The Journal of Biological Chemistry. 268 (33): 25009–14. doi:10.1016/S0021-9258(19)74564-5. PMID 7693711.
  8. ↑ ]Zong NC, Li H, Li H, Lam MP, Jimenez RC, Kim CS, Deng N, Kim AK, Choi JH, Zelaya I, Liem D, Meyer D, Odeberg J, Fang C, Lu HJ, Xu T, Weiss J, Duan H, Uhlen M, Yates JR, Apweiler R, Ge J, Hermjakob H, Ping P (Oct 2013). "Integration of cardiac proteome biology and medicine by a specialized knowledgebase". Circulation Research. 113 (9): 1043–53. doi:10.1161/CIRCRESAHA.113.301151. PMC 4076475. PMID 23965338.
  9. ↑ "Mitogen-activated protein kinase 14". Cardiac Organellar Protein Atlas Knowledgebase (COPaKB).
  10. ↑ "Entrez Gene: MAPK14 mitogen-activated protein kinase 14".
  11. 1 2 Ono K, Han J (Jan 2000). "The p38 signal transduction pathway: activation and function". Cellular Signalling. 12 (1): 1–13. doi:10.1016/s0898-6568(99)00071-6. PMID 10676842.
  12. ↑ Li M, Liu J, Zhang C (2011). "Evolutionary history of the vertebrate mitogen activated protein kinases family". PLOS ONE. 6 (10): e26999. Bibcode:2011PLoSO...626999L. doi:10.1371/journal.pone.0026999. PMC 3202601. PMID 22046431.
  13. ↑ Johnson GL, Lapadat R (Dec 2002). "Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases". Science. 298 (5600): 1911–2. Bibcode:2002Sci...298.1911J. doi:10.1126/science.1072682. PMID 12471242. S2CID 33514114.
  14. ↑ Kyriakis JM, Avruch J (Apr 2001). "Mammalian mitogen-activated protein kinase signal transduction pathways activated by stress and inflammation". Physiological Reviews. 81 (2): 807–69. doi:10.1152/physrev.2001.81.2.807. PMID 11274345.
  15. 1 2 Cuadrado A, Nebreda AR (Aug 2010). "Mechanisms and functions of p38 MAPK signalling". The Biochemical Journal. 429 (3): 403–17. doi:10.1042/BJ20100323. PMID 20626350. S2CID 9018714.
  16. ↑ Salvador JM, Mittelstadt PR, Guszczynski T, Copeland TD, Yamaguchi H, Appella E, Fornace AJ, Ashwell JD (Apr 2005). "Alternative p38 activation pathway mediated by T cell receptor-proximal tyrosine kinases". Nature Immunology. 6 (4): 390–5. doi:10.1038/ni1177. PMID 15735648. S2CID 25004892.
  17. 1 2 Ge B, Gram H, Di Padova F, Huang B, New L, Ulevitch RJ, Luo Y, Han J (Feb 2002). "MAPKK-independent activation of p38alpha mediated by TAB1-dependent autophosphorylation of p38alpha". Science. 295 (5558): 1291–4. Bibcode:2002Sci...295.1291G. doi:10.1126/science.1067289. PMID 11847341. S2CID 93896233.
  18. ↑ Tanno M, Bassi R, Gorog DA, Saurin AT, Jiang J, Heads RJ, Martin JL, Davis RJ, Flavell RA, Marber MS (Aug 2003). "Diverse mechanisms of myocardial p38 mitogen-activated protein kinase activation: evidence for MKK-independent activation by a TAB1-associated mechanism contributing to injury during myocardial ischemia". Circulation Research. 93 (3): 254–61. doi:10.1161/01.RES.0000083490.43943.85. PMID 12829618.
  19. ↑ Pillai VB, Sundaresan NR, Samant SA, Wolfgeher D, Trivedi CM, Gupta MP (Jun 2011). "Acetylation of a conserved lysine residue in the ATP binding pocket of p38 augments its kinase activity during hypertrophy of cardiomyocytes". Molecular and Cellular Biology. 31 (11): 2349–63. doi:10.1128/MCB.01205-10. PMC 3133249. PMID 21444723.
  20. 1 2 Zarubin T, Han J (Jan 2005). "Activation and signaling of the p38 MAP kinase pathway". Cell Research. 15 (1): 11–8. doi:10.1038/sj.cr.7290257. PMID 15686620.
  21. ↑ Gong X, Ming X, Deng P, Jiang Y (Aug 2010). "Mechanisms regulating the nuclear translocation of p38 MAP kinase". Journal of Cellular Biochemistry. 110 (6): 1420–9. doi:10.1002/jcb.22675. PMID 20506250. S2CID 38862126.
  22. ↑ Ben-Levy R, Hooper S, Wilson R, Paterson HF, Marshall CJ (Sep 1998). "Nuclear export of the stress-activated protein kinase p38 mediated by its substrate MAPKAP kinase-2". Current Biology. 8 (19): 1049–57. doi:10.1016/s0960-9822(98)70442-7. PMID 9768359.
  23. ↑ Hanada M, Kobayashi T, Ohnishi M, Ikeda S, Wang H, Katsura K, Yanagawa Y, Hiraga A, Kanamaru R, Tamura S (Oct 1998). "Selective suppression of stress-activated protein kinase pathway by protein phosphatase 2C in mammalian cells". FEBS Letters. 437 (3): 172–6. doi:10.1016/s0014-5793(98)01229-0. PMID 9824284.
  24. ↑ Takekawa M, Maeda T, Saito H (Aug 1998). "Protein phosphatase 2Calpha inhibits the human stress-responsive p38 and JNK MAPK pathways". The EMBO Journal. 17 (16): 4744–52. doi:10.1093/emboj/17.16.4744. PMC 1170803. PMID 9707433.
  25. ↑ Pulido R, Zúñiga A, Ullrich A (Dec 1998). "PTP-SL and STEP protein tyrosine phosphatases regulate the activation of the extracellular signal-regulated kinases ERK1 and ERK2 by association through a kinase interaction motif". The EMBO Journal. 17 (24): 7337–50. doi:10.1093/emboj/17.24.7337. PMC 1171079. PMID 9857190.
  26. ↑ Saxena M, Williams S, Brockdorff J, Gilman J, Mustelin T (Apr 1999). "Inhibition of T cell signaling by mitogen-activated protein kinase-targeted hematopoietic tyrosine phosphatase (HePTP)". The Journal of Biological Chemistry. 274 (17): 11693–700. doi:10.1074/jbc.274.17.11693. PMID 10206983.
  27. ↑ Saxena M, Williams S, Gilman J, Mustelin T (Jun 1998). "Negative regulation of T cell antigen receptor signal transduction by hematopoietic tyrosine phosphatase (HePTP)". The Journal of Biological Chemistry. 273 (25): 15340–4. doi:10.1074/jbc.273.25.15340. PMID 9624114.
  28. ↑ Ota A, Zhang J, Ping P, Han J, Wang Y (Apr 2010). "Specific regulation of noncanonical p38alpha activation by Hsp90-Cdc37 chaperone complex in cardiomyocyte". Circulation Research. 106 (8): 1404–12. doi:10.1161/CIRCRESAHA.109.213769. PMC 2891038. PMID 20299663.
  29. ↑ Young PR (Dec 2013). "Perspective on the discovery and scientific impact of p38 MAP kinase". Journal of Biomolecular Screening. 18 (10): 1156–63. doi:10.1177/1087057113497401. PMID 23896688.
  30. ↑ Rose BA, Force T, Wang Y (Oct 2010). "Mitogen-activated protein kinase signaling in the heart: angels versus demons in a heart-breaking tale". Physiological Reviews. 90 (4): 1507–46. doi:10.1152/physrev.00054.2009. PMC 3808831. PMID 20959622.
  31. ↑ Raingeaud J, Gupta S, Rogers JS, Dickens M, Han J, Ulevitch RJ, Davis RJ (Mar 1995). "Pro-inflammatory cytokines and environmental stress cause p38 mitogen-activated protein kinase activation by dual phosphorylation on tyrosine and threonine". The Journal of Biological Chemistry. 270 (13): 7420–6. doi:10.1074/jbc.270.13.7420. PMID 7535770.
  32. ↑ Vlahopoulos SA, Logotheti S, Mikas D, Giarika A, Gorgoulis V, Zoumpourlis V (Apr 2008). "The role of ATF-2 in oncogenesis". BioEssays. 30 (4): 314–27. doi:10.1002/bies.20734. PMID 18348191. S2CID 678541.
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  34. ↑ Breitwieser W, Lyons S, Flenniken AM, Ashton G, Bruder G, Willington M, Lacaud G, Kouskoff V, Jones N (Aug 2007). "Feedback regulation of p38 activity via ATF2 is essential for survival of embryonic liver cells". Genes & Development. 21 (16): 2069–82. doi:10.1101/gad.430207. PMC 1948861. PMID 17699753.
  35. ↑ Engel FB, Schebesta M, Keating MT (Oct 2006). "Anillin localization defect in cardiomyocyte binucleation". Journal of Molecular and Cellular Cardiology. 41 (4): 601–12. doi:10.1016/j.yjmcc.2006.06.012. PMID 16889791.
  36. ↑ Engel FB, Hsieh PC, Lee RT, Keating MT (Oct 2006). "FGF1/p38 MAP kinase inhibitor therapy induces cardiomyocyte mitosis, reduces scarring, and rescues function after myocardial infarction". Proceedings of the National Academy of Sciences of the United States of America. 103 (42): 15546–51. Bibcode:2006PNAS..10315546E. doi:10.1073/pnas.0607382103. PMC 1622860. PMID 17032753.
  37. ↑ Engel FB, Schebesta M, Duong MT, Lu G, Ren S, Madwed JB, Jiang H, Wang Y, Keating MT (May 2005). "p38 MAP kinase inhibition enables proliferation of adult mammalian cardiomyocytes". Genes & Development. 19 (10): 1175–87. doi:10.1101/gad.1306705. PMC 1132004. PMID 15870258.
  38. ↑ Kaiser RA, Bueno OF, Lips DJ, Doevendans PA, Jones F, Kimball TF, Molkentin JD (Apr 2004). "Targeted inhibition of p38 mitogen-activated protein kinase antagonizes cardiac injury and cell death following ischemia-reperfusion in vivo". The Journal of Biological Chemistry. 279 (15): 15524–30. doi:10.1074/jbc.M313717200. PMID 14749328.
  39. ↑ Sharov VG, Todor A, Suzuki G, Morita H, Tanhehco EJ, Sabbah HN (Mar 2003). "Hypoxia, angiotensin-II, and norepinephrine mediated apoptosis is stimulus specific in canine failed cardiomyocytes: a role for p38 MAPK, Fas-L and cyclin D1". European Journal of Heart Failure. 5 (2): 121–9. doi:10.1016/s1388-9842(02)00254-4. PMID 12644001. S2CID 21917525.
  40. ↑ Eiras S, Fernández P, Piñeiro R, Iglesias MJ, González-Juanatey JR, Lago F (Jul 2006). "Doxazosin induces activation of GADD153 and cleavage of focal adhesion kinase in cardiomyocytes en route to apoptosis". Cardiovascular Research. 71 (1): 118–28. doi:10.1016/j.cardiores.2006.03.014. PMID 16631627.
  41. ↑ Fiordaliso F, Leri A, Cesselli D, Limana F, Safai B, Nadal-Ginard B, Anversa P, Kajstura J (Oct 2001). "Hyperglycemia activates p53 and p53-regulated genes leading to myocyte cell death". Diabetes. 50 (10): 2363–75. doi:10.2337/diabetes.50.10.2363. PMID 11574421.
  42. ↑ Ghosh J, Das J, Manna P, Sil PC (Oct 2009). "Taurine prevents arsenic-induced cardiac oxidative stress and apoptotic damage: role of NF-kappa B, p38 and JNK MAPK pathway". Toxicology and Applied Pharmacology. 240 (1): 73–87. doi:10.1016/j.taap.2009.07.008. PMID 19616567.
  43. ↑ Qian J, Ling S, Castillo AC, Long B, Birnbaum Y, Ye Y (May 2012). "Regulation of phosphatase and tensin homolog on chromosome 10 in response to hypoxia". American Journal of Physiology. Heart and Circulatory Physiology. 302 (9): H1806–17. doi:10.1152/ajpheart.00929.2011. PMID 22367504.
  44. ↑ Schröder D, Heger J, Piper HM, Euler G (Nov 2006). "Angiotensin II stimulates apoptosis via TGF-beta1 signaling in ventricular cardiomyocytes of rat". Journal of Molecular Medicine. 84 (11): 975–83. doi:10.1007/s00109-006-0090-0. PMID 16924465. S2CID 12670283.
  45. ↑ Stephanou A, Scarabelli TM, Brar BK, Nakanishi Y, Matsumura M, Knight RA, Latchman DS (Jul 2001). "Induction of apoptosis and Fas receptor/Fas ligand expression by ischemia/reperfusion in cardiac myocytes requires serine 727 of the STAT-1 transcription factor but not tyrosine 701". The Journal of Biological Chemistry. 276 (30): 28340–7. doi:10.1074/jbc.M101177200. PMID 11309387.
  46. ↑ Zhao D, Chu WF, Wu L, Li J, Liu QM, Lu YJ, Qiao GF, Wang ZG, Zhang ZR, Yang BF (Aug 2010). "PAF exerts a direct apoptotic effect on the rat H9c2 cardiomyocytes in Ca2+-dependent manner". International Journal of Cardiology. 143 (1): 86–93. doi:10.1016/j.ijcard.2009.01.068. PMID 19237210.
  47. ↑ Qi Y, Xu Z, Zhu Q, Thomas C, Kumar R, Feng H, Dostal DE, White MF, Baker KM, Guo S (Nov 2013). "Myocardial loss of IRS1 and IRS2 causes heart failure and is controlled by p38α MAPK during insulin resistance". Diabetes. 62 (11): 3887–900. doi:10.2337/db13-0095. PMC 3806607. PMID 24159000.
  48. ↑ Ma XL, Kumar S, Gao F, Louden CS, Lopez BL, Christopher TA, Wang C, Lee JC, Feuerstein GZ, Yue TL (Apr 1999). "Inhibition of p38 mitogen-activated protein kinase decreases cardiomyocyte apoptosis and improves cardiac function after myocardial ischemia and reperfusion". Circulation. 99 (13): 1685–91. doi:10.1161/01.cir.99.13.1685. PMID 10190877.
  49. ↑ Ren J, Zhang S, Kovacs A, Wang Y, Muslin AJ (Apr 2005). "Role of p38alpha MAPK in cardiac apoptosis and remodeling after myocardial infarction". Journal of Molecular and Cellular Cardiology. 38 (4): 617–23. doi:10.1016/j.yjmcc.2005.01.012. PMID 15808838.
  50. ↑ Aggeli IK, Beis I, Gaitanaki C (Jul 2008). "Oxidative stress and calpain inhibition induce alpha B-crystallin phosphorylation via p38 MAPK and calcium signalling pathways in H9c2 cells". Cellular Signalling. 20 (7): 1292–302. doi:10.1016/j.cellsig.2008.02.019. PMID 18420382.
  51. ↑ Liu D, He M, Yi B, Guo WH, Que AL, Zhang JX (Nov 2009). "Pim-3 protects against cardiomyocyte apoptosis in anoxia/reoxygenation injury via p38-mediated signal pathway". The International Journal of Biochemistry & Cell Biology. 41 (11): 2315–22. doi:10.1016/j.biocel.2009.05.021. PMID 19505587.
  52. ↑ Mitra A, Ray A, Datta R, Sengupta S, Sarkar S (Sep 2014). "Cardioprotective role of P38 MAPK during myocardial infarction via parallel activation of α-crystallin B and Nrf2". Journal of Cellular Physiology. 229 (9): 1272–82. doi:10.1002/jcp.24565. PMID 24464634. S2CID 10718645.
  53. 1 2 Wang Y, Huang S, Sah VP, Ross J, Brown JH, Han J, Chien KR (Jan 1998). "Cardiac muscle cell hypertrophy and apoptosis induced by distinct members of the p38 mitogen-activated protein kinase family". The Journal of Biological Chemistry. 273 (4): 2161–8. doi:10.1074/jbc.273.4.2161. PMID 9442057.
  54. ↑ Kim JK, Pedram A, Razandi M, Levin ER (Mar 2006). "Estrogen prevents cardiomyocyte apoptosis through inhibition of reactive oxygen species and differential regulation of p38 kinase isoforms". The Journal of Biological Chemistry. 281 (10): 6760–7. doi:10.1074/jbc.M511024200. PMID 16407188.
  55. ↑ Liu H, Pedram A, Kim JK (Jan 2011). "Oestrogen prevents cardiomyocyte apoptosis by suppressing p38α-mediated activation of p53 and by down-regulating p53 inhibition on p38β". Cardiovascular Research. 89 (1): 119–28. doi:10.1093/cvr/cvq265. PMC 3002868. PMID 20724307.
  56. ↑ Marber MS, Rose B, Wang Y (Oct 2011). "The p38 mitogen-activated protein kinase pathway--a potential target for intervention in infarction, hypertrophy, and heart failure". Journal of Molecular and Cellular Cardiology. 51 (4): 485–90. doi:10.1016/j.yjmcc.2010.10.021. PMC 3061241. PMID 21062627.
  57. ↑ Liang Q, Molkentin JD (Dec 2003). "Redefining the roles of p38 and JNK signaling in cardiac hypertrophy: dichotomy between cultured myocytes and animal models". Journal of Molecular and Cellular Cardiology. 35 (12): 1385–94. doi:10.1016/j.yjmcc.2003.10.001. PMID 14654364.
  58. ↑ Nemoto S, Sheng Z, Lin A (Jun 1998). "Opposing effects of Jun kinase and p38 mitogen-activated protein kinases on cardiomyocyte hypertrophy". Molecular and Cellular Biology. 18 (6): 3518–26. doi:10.1128/mcb.18.6.3518. PMC 108933. PMID 9584192.
  59. ↑ Zechner D, Thuerauf DJ, Hanford DS, McDonough PM, Glembotski CC (Oct 1997). "A role for the p38 mitogen-activated protein kinase pathway in myocardial cell growth, sarcomeric organization, and cardiac-specific gene expression". The Journal of Cell Biology. 139 (1): 115–27. doi:10.1083/jcb.139.1.115. PMC 2139826. PMID 9314533.
  60. ↑ Liao P, Georgakopoulos D, Kovacs A, Zheng M, Lerner D, Pu H, Saffitz J, Chien K, Xiao RP, Kass DA, Wang Y (Oct 2001). "The in vivo role of p38 MAP kinases in cardiac remodeling and restrictive cardiomyopathy". Proceedings of the National Academy of Sciences of the United States of America. 98 (21): 12283–8. Bibcode:2001PNAS...9812283L. doi:10.1073/pnas.211086598. PMC 59806. PMID 11593045.
  61. ↑ Nishida K, Yamaguchi O, Hirotani S, Hikoso S, Higuchi Y, Watanabe T, Takeda T, Osuka S, Morita T, Kondoh G, Uno Y, Kashiwase K, Taniike M, Nakai A, Matsumura Y, Miyazaki J, Sudo T, Hongo K, Kusakari Y, Kurihara S, Chien KR, Takeda J, Hori M, Otsu K (Dec 2004). "p38alpha mitogen-activated protein kinase plays a critical role in cardiomyocyte survival but not in cardiac hypertrophic growth in response to pressure overload". Molecular and Cellular Biology. 24 (24): 10611–20. doi:10.1128/MCB.24.24.10611-10620.2004. PMC 533965. PMID 15572667.
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