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GADD45 outline of changes

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Function

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Gadd45g has several different functions in humans, including sexual development,[1] human-specific brain development,[2] tumor suppression,[3] and the cellular stress response.[4] In general, Gadd45g interacts with several other proteins that are involved in DNA repair, cell cycle control, apoptosis, and senescence.[5]

In the male sexual development pathway, Gadd45g is essential for activating SRY, leading to proper formation of the gonads and sex-determination.[6] Deletion of an enhancer close to the Gadd45g gene is correlated to increased proliferation of neuronal cells, which could account for part of the difference in neural development between humans and other species.[7] After DNA damage, Gadd45g helps to prevent tumor formation by its apoptosis-inducing interactions with the MTK/MEKK4 kinases, which are upstream of p38/JNK. Gadd45g is in turn regulated upstream by NF-κB. It it also involved in repression of the cell cycle through the G2/M checkpoint.[8]

Interactions

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GADD45G is involved with dental epithelial cell proliferation. GADD45g regulates cell proliferation and gene expression where it is an active gene. GADD45G is expressed in enamel knots. The gene regulates p21-mediated epithelial cell proliferation by activating the p38 MAPK pathway during the development of teeth.[9]

Clinical Significance

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Generally, in numerous kinds of cancerous cells, GADD45G is down regulated.[10] There is a low expression due to methylation of the GADD45G promotor.[11]

GADD45G is related to esophageal cancer. GADD45G is silenced by methylation in these cancer cells. The expression level and methylation status are involved in the prognosis of esophageal squamous cell carcinoma. Demethylation of the gene may have a therapeutic advantage in esophageal cancer.[12]

In hepatocellular carcinoma cells GADD45G is down regulated.It participates in negatively regulating the Jak-Stat3 signaling pathway. It acts as a tumor suppressor in HCC cells by inducing growth arrest or cellular senescence. When GADD45G expression is low, liver cells may be able to avoid the growth arrest stage of the cell life cycle.[13]

Human Tissue Distribution

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GADD45G is expressed most in the skeletal muscle, kidney and liver. This gene has a low expression in the heart, brain, spleen, lung and testis.[14]

Discovery

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GADD45G was originally cloned by Beadling under the name CR6 in 1993,[15] and its function as a tumor suppressor was discovered in 1999 by Zhang.[16]

Bibliography

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Tamura RE, de Vasconcellos JF, Sarkar D, Libermann TA, Fisher PB, Zerbini LF (June 2012). "GADD45 proteins: central players in tumorigenesis". Curr. Mol. Med. 12 (5): 634–51. doi:10.2174/156652412800619978. PMC 3797964. PMID 22515981.{{cite journal}}: CS1 maint: date and year (link) CS1 maint: multiple names: authors list (link)

Moskalev AA, Smit-McBride Z, Shaposhnikov MV; et al. (January 2012). "Gadd45 proteins: relevance to aging, longevity and age-related pathologies". Ageing Res. Rev. 11 (1): 51–66. doi:10.1016/j.arr.2011.09.003. PMC 3765067. PMID 21986581. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: date and year (link) CS1 maint: multiple names: authors list (link)

Yang Z, Song L, Huang C (December 2009). "Gadd45 proteins as critical signal transducers linking NF-kappaB to MAPK cascades". Curr Cancer Drug Targets. 9 (8): 915–30. doi:10.2174/156800909790192383. PMC 3762688. PMID 20025601.{{cite journal}}: CS1 maint: date and year (link) CS1 maint: multiple names: authors list (link)

Liebermann DA, Hoffman B (2007). "Gadd45 in the response of hematopoietic cells to genotoxic stress". Blood Cells Mol. Dis. 39 (3): 329–35. doi:10.1016/j.bcmd.2007.06.006. PMC 3268059. PMID 17659913.

Liebermann DA, Tront JS, Sha X, Mukherjee K, Mohamed-Hadley A, Hoffman B (2011). "Gadd45 stress sensors in malignancy and leukemia". Crit Rev Oncog. 16 (1–2): 129–40. doi:10.1615/critrevoncog.v16.i1-2.120. PMC 3268054. PMID 22150313.{{cite journal}}: CS1 maint: multiple names: authors list (link)

Lu B (2006). "The molecular mechanisms that control function and death of effector CD4+ T cells". Immunol. Res. 36 (1–3): 275–82. doi:10.1385/IR:36:1:275. PMID 17337788.

Papa S, Zazzeroni F, Pham CG, Bubici C, Franzoso G (October 2004). "Linking JNK signaling to NF-kappaB: a key to survival". J. Cell. Sci. 117 (Pt 22): 5197–208. doi:10.1242/jcs.01483. PMID 15483317.{{cite journal}}: CS1 maint: date and year (link) CS1 maint: multiple names: authors list (link)

McLean CY, Reno PL, Pollen AA; et al. (March 2011). "Human-specific loss of regulatory DNA and the evolution of human-specific traits". Nature. 471 (7337): 216–9. doi:10.1038/nature09774. PMC 3071156. PMID 21390129. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: date and year (link) CS1 maint: multiple names: authors list (link)

Johnen H, González-Silva L, Carramolino L, Flores JM, Torres M, Salvador JM (2013). "Gadd45g is essential for primary sex determination, male fertility and testis development". PLOS ONE. 8 (3): e58751. doi:10.1371/journal.pone.0058751. PMC 3596291. PMID 23516551.{{cite journal}}: CS1 maint: multiple names: authors list (link)

Gierl MS, Gruhn WH, von Seggern A, Maltry N, Niehrs C (November 2012). "GADD45G functions in male sex determination by promoting p38 signaling and Sry expression". Dev. Cell. 23 (5): 1032–42. doi:10.1016/j.devcel.2012.09.014. PMID 23102581.{{cite journal}}: CS1 maint: date and year (link) CS1 maint: multiple names: authors list (link)

Flores O, Burnstein KL (October 2010). "GADD45gamma: a new vitamin D-regulated gene that is antiproliferative in prostate cancer cells". Endocrinology. 151 (10): 4654–64. doi:10.1210/en.2010-0434. PMC 2946153. PMID 20739400.{{cite journal}}: CS1 maint: date and year (link)

Cited References

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  1. ^ Johnen H, González-Silva L, Carramolino L, Flores JM, Torres M, Salvador JM (2013). "Gadd45g is essential for primary sex determination, male fertility and testis development". PLOS ONE. 8 (3): e58751. doi:10.1371/journal.pone.0058751. PMC 3596291. PMID 23516551.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  2. ^ McLean CY, Reno PL, Pollen AA; et al. (March 2011). "Human-specific loss of regulatory DNA and the evolution of human-specific traits". Nature. 471 (7337): 216–9. doi:10.1038/nature09774. PMC 3071156. PMID 21390129. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: date and year (link) CS1 maint: multiple names: authors list (link)
  3. ^ Tamura RE, de Vasconcellos JF, Sarkar D, Libermann TA, Fisher PB, Zerbini LF (June 2012). "GADD45 proteins: central players in tumorigenesis". Curr. Mol. Med. 12 (5): 634–51. doi:10.2174/156652412800619978. PMC 3797964. PMID 22515981.{{cite journal}}: CS1 maint: date and year (link) CS1 maint: multiple names: authors list (link)
  4. ^ Liebermann DA, Hoffman B (2007). "Gadd45 in the response of hematopoietic cells to genotoxic stress". Blood Cells Mol. Dis. 39 (3): 329–35. doi:10.1016/j.bcmd.2007.06.006. PMC 3268059. PMID 17659913.
  5. ^ Johnen H, González-Silva L, Carramolino L, Flores JM, Torres M, Salvador JM (2013). "Gadd45g is essential for primary sex determination, male fertility and testis development". PLOS ONE. 8 (3): e58751. doi:10.1371/journal.pone.0058751. PMC 3596291. PMID 23516551.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  6. ^ Johnen H, González-Silva L, Carramolino L, Flores JM, Torres M, Salvador JM (2013). "Gadd45g is essential for primary sex determination, male fertility and testis development". PLOS ONE. 8 (3): e58751. doi:10.1371/journal.pone.0058751. PMC 3596291. PMID 23516551.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  7. ^ McLean CY, Reno PL, Pollen AA; et al. (March 2011). "Human-specific loss of regulatory DNA and the evolution of human-specific traits". Nature. 471 (7337): 216–9. doi:10.1038/nature09774. PMC 3071156. PMID 21390129. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: date and year (link) CS1 maint: multiple names: authors list (link)
  8. ^ Tamura RE, de Vasconcellos JF, Sarkar D, Libermann TA, Fisher PB, Zerbini LF (June 2012). "GADD45 proteins: central players in tumorigenesis". Curr. Mol. Med. 12 (5): 634–51. doi:10.2174/156652412800619978. PMC 3797964. PMID 22515981.{{cite journal}}: CS1 maint: date and year (link) CS1 maint: multiple names: authors list (link)
  9. ^ Ishida K, Yuge Y, Hanaoka M; et al. (August 2013). "Gadd45g regulates dental epithelial cell proliferation through p38 MAPK-mediated p21 expression". Genes Cells. 18 (8): 660–71. doi:10.1111/gtc.12067. PMID 23751077. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: date and year (link) CS1 maint: multiple names: authors list (link)
  10. ^ Zhang L, Yang Z, Ma A; et al. (January 2014). "Growth arrest and DNA damage 45G down-regulation contributes to Janus kinase/signal transducer and activator of transcription 3 activation and cellular senescence evasion in hepatocellular carcinoma". Hepatology. 59 (1): 178–89. doi:10.1002/hep.26628. PMID 23897841. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: date and year (link) CS1 maint: multiple names: authors list (link)
  11. ^ Ishida K, Yuge Y, Hanaoka M; et al. (August 2013). "Gadd45g regulates dental epithelial cell proliferation through p38 MAPK-mediated p21 expression". Genes Cells. 18 (8): 660–71. doi:10.1111/gtc.12067. PMID 23751077. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: date and year (link) CS1 maint: multiple names: authors list (link)
  12. ^ Ishida K, Yuge Y, Hanaoka M; et al. (August 2013). "Gadd45g regulates dental epithelial cell proliferation through p38 MAPK-mediated p21 expression". Genes Cells. 18 (8): 660–71. doi:10.1111/gtc.12067. PMID 23751077. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: date and year (link) CS1 maint: multiple names: authors list (link)
  13. ^ Zhang L, Yang Z, Ma A; et al. (January 2014). "Growth arrest and DNA damage 45G down-regulation contributes to Janus kinase/signal transducer and activator of transcription 3 activation and cellular senescence evasion in hepatocellular carcinoma". Hepatology. 59 (1): 178–89. doi:10.1002/hep.26628. PMID 23897841. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: date and year (link) CS1 maint: multiple names: authors list (link)
  14. ^ Tamura RE, de Vasconcellos JF, Sarkar D, Libermann TA, Fisher PB, Zerbini LF (June 2012). "GADD45 proteins: central players in tumorigenesis". Curr. Mol. Med. 12 (5): 634–51. PMC 3797964. PMID 22515981.
  15. ^ C. Beadling, K. W. Johnson & K. A. Smith (April 1993). "Isolation of interleukin 2-induced immediate-early genes". Proceedings of the National Academy of Sciences of the United States of America. 90 (7): 2719–2723. doi:10.1073/pnas.90.7.2719. PMC 46167. PMID 7681987.{{cite journal}}: CS1 maint: date and year (link)
  16. ^ W. Zhang, I. Bae, K. Krishnaraju, N. Azam, W. Fan, K. Smith, B. Hoffman & D. A. Liebermann (September 1999). "CR6: A third member in the MyD118 and Gadd45 gene family which functions in negative growth control". Oncogene. 18 (35): 4899–4907. doi:10.1038/sj.onc.1202885. PMID 10490824.{{cite journal}}: CS1 maint: date and year (link) CS1 maint: multiple names: authors list (link)
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