atm john berry. what is atm? named “atm” for “ataxia-telangiectasia mutated” gene. the...
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ATMATM
John BerryJohn Berry
What is ATM?What is ATM? Named “ATM” for “Ataxia-telangiectasia Named “ATM” for “Ataxia-telangiectasia
Mutated” gene. The mutation is Mutated” gene. The mutation is recessive.recessive.
Ataxia-telangiectasia (or AT) is a Ataxia-telangiectasia (or AT) is a neurodegenerative disease that is neurodegenerative disease that is normally detected in infancy to early normally detected in infancy to early childhood. childhood.
AT patients have shown a predisposition AT patients have shown a predisposition to Lymphoma, so ATM was suspected as to Lymphoma, so ATM was suspected as a tumor suppressing gene.a tumor suppressing gene.
http://my.webmd.com/hw/health_guide_atoz/nord406.asphttp://my.webmd.com/hw/health_guide_atoz/nord406.asp
AT SymptomsAT Symptoms
Symptoms: ataxia, telangiectasia, Symptoms: ataxia, telangiectasia, and impairing of the immune systemand impairing of the immune system
http://my.webmd.com/hw/health_guide_atoz/nord406.asphttp://my.webmd.com/hw/health_guide_atoz/nord406.asp
AT SymptomsAT Symptoms
Symptoms: ataxia, telangiectasia, Symptoms: ataxia, telangiectasia, and impairing of the immune systemand impairing of the immune system
http://www.uv.es/derma/CLindex/CLlinfomas/CLmast9.jpghttp://www.uv.es/derma/CLindex/CLlinfomas/CLmast9.jpg
http://my.webmd.com/hw/health_guide_atoz/nord406.asphttp://my.webmd.com/hw/health_guide_atoz/nord406.asp
AT EffectsAT Effects
Patients are subject to Patients are subject to sinopulmonary infections sinopulmonary infections
Increased occurrence of malignant Increased occurrence of malignant tumors.tumors.
Patients have a short life-Patients have a short life-expectancy.expectancy.
http://my.webmd.com/hw/health_guide_atoz/nord406.asphttp://my.webmd.com/hw/health_guide_atoz/nord406.asp
ATMATM
P(3)IK Serine-Threonine KinaseP(3)IK Serine-Threonine Kinase Located in the NucleusLocated in the Nucleus Normally inactivatedNormally inactivated Rapid activation in response to Rapid activation in response to
Double Strand Break (DSB)Double Strand Break (DSB) Substrate list is not presently Substrate list is not presently
complete.complete.
ATM Function ATM Function http://jncicancerspectrum.oupjournals.org.libproxy.lib.unc.edu/cgi/reprint/jnci;92/10/795.pdfhttp://jncicancerspectrum.oupjournals.org.libproxy.lib.unc.edu/cgi/reprint/jnci;92/10/795.pdf
ATM SubstratesATM Substrateshttp://jncicancerspectrum.oupjournals.org.libproxy.lib.unc.edu/cgi/reprint/jnci;92/10/795.pdfhttp://jncicancerspectrum.oupjournals.org.libproxy.lib.unc.edu/cgi/reprint/jnci;92/10/795.pdf
ATM Checkpoint FunctionsATM Checkpoint FunctionsShiloh, Yosef. “ATM AND RELATED PROTEIN KINASES: SAFEGUARDING GENOMEINTEGRITY.” Nature Reviews Cancer. Volume 3 March
2003 pg 155-168
RepairRepairMcKinnon, Peter J. “ATM and Ataxia telangiectasia.”McKinnon, Peter J. “ATM and Ataxia telangiectasia.”EmboEmbo Reports.Reports. Vol 3 (8) 2004. Vol 3 (8) 2004.
pg 772-776pg 772-776
ATM knockout in MiceATM knockout in Mice
ATM -/-: Lymphoma in 2-4 monthsATM -/-: Lymphoma in 2-4 months
Heterozygous mice are predisposed.Heterozygous mice are predisposed.
Loss of Heterozygosity is required in Loss of Heterozygosity is required in mostmost cases cases
Barlow, C, et al. “Atm-deficient mice: a paradigm of ataxia telangiectasia. Barlow, C, et al. “Atm-deficient mice: a paradigm of ataxia telangiectasia. CellCell. .
1996 Jul 12;86(1):159-71.1996 Jul 12;86(1):159-71.
Evidence for the PathwayEvidence for the Pathwayhttp://breast-cancer-research.com/content/pdf/bcr968.pdfhttp://breast-cancer-research.com/content/pdf/bcr968.pdf
ATM +/-, p53 +/- MiceATM +/-, p53 +/- Mice
Irradiated Irradiated double double heterozygoheterozygous mice us mice show the show the highest highest incidence of incidence of carcinogenecarcinogenesissis
http://breast-cancer-http://breast-cancer-research.com/content/pdf/research.com/content/pdf/bcr968.pdfbcr968.pdf
ATM mutations in Human ATM mutations in Human CancerCancer
A-T Patients are not the main health A-T Patients are not the main health concern, but rather carriers of A-T.concern, but rather carriers of A-T.
Most heterozygous individuals do Most heterozygous individuals do not show a pre-disposition to cancernot show a pre-disposition to cancer
Discovery of the dominant negativeDiscovery of the dominant negative
Shiloh, Yosef. “ATM AND RELATED PROTEIN KINASES: SAFEGUARDING GENOMEINTEGRITY.” Nature Reviews Cancer. Volume 3 March 2003 pg 155-168
ATM Function ATM Function http://jncicancerspectrum.oupjournals.org.libproxy.lib.unc.edu/cgi/reprint/jnci;92/10/795.pdfhttp://jncicancerspectrum.oupjournals.org.libproxy.lib.unc.edu/cgi/reprint/jnci;92/10/795.pdf
Future DirectionsFuture Directions
Despite a limited risk group, ATM is Despite a limited risk group, ATM is still important for research.still important for research.
Damage repair is a key component Damage repair is a key component of homeostasis.of homeostasis.
Any Questions?Any Questions?