IN SMALL CELL LUNG CANCER ONE CANNOT OVER-EMPHASIZE THE ROLE OF SOX2 GENE!

IT IS A GENE THAT LEADS TO ORGAN DEVELOPMENT (EYES), ANOPHTHALMIA SYNDROME, MICROPHTHALMIA, SEPTO-OPTIC DYSPLASIA
 LOCATION 3q26  (NOTE THE Q)
IF IT INVOLVES ORGAN DEVELOPMENT, REMEMBER THALIDOMID AND ANTI-ANGIOGENIC DRUGS EFFECT!

SOX2

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SRY (sex determining region Y)-box 2
PDB rendering based on 1gt0.
Available structures PDB Ortholog search: PDBe, RCSB [show]List of PDB id codes
Identifiers
Symbols	SOX2; ANOP3; MCOPS3
External IDs	OMIM: 184429 MGI: 98364 HomoloGene: 68298 GeneCards: SOX2 Gene
[show]Gene Ontology
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	6657	20674
Ensembl	ENSG00000181449	ENSMUSG00000074637
UniProt	P48431	P48432
RefSeq (mRNA)	NM_003106	NM_011443
RefSeq (protein)	NP_003097	NP_035573
Location (UCSC)	Chr 3: 181.43 – 181.43 Mb	Chr 3: 34.65 – 34.65 Mb
PubMed search	[1]	[2]
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SRY (sex determining region Y)-box 2, also known as SOX2, is a transcription factor that is essential for maintaining self-renewal, or pluripotency, of undifferentiated embryonic stem cells. Sox2 is a member of the Sox family of transcription factors, which have been shown to play key roles in many stages of mammalian development. This protein family shares highly conserved DNA binding domains known as HMG (High-mobility group) box domains containing approximately 80 amino acids. Sox2 has a critical role in maintenance of embryonic and neural stem cells and holds great promise in research involving induced pluripotency, an emerging and very promising field of regenerative medicine.^[1]

Contents 1 Function and expression in pluripotency 2 Role in neural stem cells 3 Interactions 4 Clinical significance 5 Eye deformities 5.1 Cancer 6 References 7 Further reading 8 External links

Function and expression in pluripotency

LIF (Leukemia inhibitory factor) signaling, which maintains pluripotency in mouse embryonic stem cells, activates Sox2 downstream of the JAK-STAT signaling pathway and subsequent activation of Klf4 (a member of the family of Kruppel-like factors). Oct-4, Sox2 and Nanog positively regulate transcription of all pluripotency circuitry proteins in the LIF pathway.^[2]In an experiment involving mouse embryonic stem cells, it was discovered that Sox2 in conjunction with Oct4, c-Myc and Klf4 were sufficient for producing induced pluripotent stem cells.^[6] The discovery that expression of only four transcription factors was necessary to induce pluripotency allowed future regenerative medicine research to be conducted considering minor manipulations.
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Its association with NM1  increase its amplification.
Here you find the role of JAK-STAT pathway as prominent in SCLC.
You also find understand why this propensity to CNS metastasis
They did not say anything about MEK, the door to dedifferentiation!
It forms a complex with OCT4
and interacts with  YES1, FGF4, UTF1 and ZFP206 (By similarity)
and with  . Downstream

SRRT target that mediates the promotion of neural stem cell self-renewal (By similarity). Keeps neural cells undifferentiated by counteracting the activity of proneural proteins and suppresses neuronal differentiation (By similarity)

Subunit: Interacts with ZSCAN10 (By similarity). Interacts with SOX3 and FGFR1 (By similarity) Subcellular location: Nucleus Biotechnology: POU5F1/OCT4, SOX2, MYC/c-Myc and KLF4 are the four Yamanaka factors.

 
--------------------------------------------------------------This gene lies within an intron of another gene called SOX2 overlapping transcript (SOX2OT). The importance of SOX2 and OCT4 as regulators of pluripotency has been dramatically illustrated by the demonstration that these factors together with c-Myc and Klf4 or Nanog and LIN28 can induce the dedifferentiation of somatic cells into induced pluripotent stem cells (iPS) with many of the features of embryonic stem cells, Takahashi, K. and Yamanaka, S. (2006); Wernig, M. et al. (2007) and Yu, J. et al. (2007).

  Nanog is also a very important early regulator of pluripotency. Together SOX2, OCT4 and Nanog co-regulate a growing list of downstream target genes. Target genes include YES1, FGF4, UTF1, Fbx15, Zic3 and ZFP206, but this is only a sampling of the hundreds of genes that are involved. The targets of SOX2, OCT4 and Nanog have recently been identified using time course microarray and genome-wide immunoprecipition data, Sharov, A.A, et al. (2008).
Loss of function SOX2 mutations have been linked to the rare disease microphthalmia syndrome type 3, small eye, (MCOPS3), Ragge NK, et al. (2005); Verma, A.S, and Fitzpatrick, D.R. (2007.)
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(Chen et al.) SOX2 contributes to the tumorigenesis of lung cancer cells and can be used as a diagnostic probe. In addition, obviously higher expression of oncogenes c-MYC, WNT1, WNT2, and NOTCH1,  AND YOU KNOW THAT IF YOU TOUCH THE WNT , YOU FIGHT VIGOROUSLY BREAST CANCER!  OPENING UP SOX2 AS A MAJOR TARGET IN BREAST AND LUNG CANCERS!
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IF YOU DO NOT FIND A TARGET THERAPY, DREAM AGAIN!
REMEMBER THIS WHERE ANTI-HISTONE DEACYL TRANSFERASE INHIBITOR COMES HANDY!  AND YOU GUESSED IT, SOME ANTIBIOTIC FROM FUNGI WHICH ATTACK TRANSCRIPTION FACTORS.

WAKE UP AND SMELL THE COFFEE.  THE STORY OF DDR2

ONE OF THE MOST POWERFUL PAPERS

« ASCO issues Provisional Clinical Opinion on EGFR testing in Non-Small-Cell Lung Cancer | Main | Systems biology for studying cancer »

May 06, 2011

DDR2 Kinase Mutations in Lung Squamous Cell Carcinoma

Yes--you read that right!
The journal Cancer Discovery reports in a publish ahead-of-print article (abstract) the discovery of mutations in the discoidin domain receptor 2 tyrosine kinase (DDR2) gene in a series of lung squamous cell carcinomas (SQC) that may identify a  potential therapeutic target similar to those described for lung adenocarcinomas.  Interestingly, DDR2 is a receptor kinase that normally binds collagen as its ligand and has been shown to promote cell migration, proliferation, and survival when activated by ligand binding and phosphorylation.
While subtypes of lung adenocarcinoma (ADC) have been increasingly better defined and characterized on multiple levels with respect to identifying therapeutic targets/responses, minimal progress has been made with squamous cell carcinoma.
The authors of this study used conventional Sanger sequencing of 201 genes, including the entire tyrosine kinome, in an initial set of 20 primary lung SQC and matched normal controls and identified 2 samples with DDR2 mutations; a secondary screen of 48 lung SQC samples identified an additional 4 DDR2 mutations.  Following this, the authors sequenced DDR2 in a validation cohort of 222 primary lung SQC samples and identified 5 additional samples with mutations.  Excluding samples from lung SQC cell lines, there was an overall frequency of 3.2% of DDR2 mutations in primary lung SQC samples--about the same frequency reported for ALK fusion mutations in lung ADC.
The authors analyzed the TKIs imatinib and dasatinib, previously reported to inhibit DDR2, to evaluate whether targeting DDR2 mutated in SQC might be a potential therapeutic strategy.  Dasatinib showed particular efficacy in inhibiting proliferation and promoting cell death through apoptosis in SQC cell ines with DDR2 mutations.  In addition, they report one of 7 subjects from an early-phase trial of dasatinib or combination dasatinib and erlotinib with advanced stage lung SQC cancer who exhibited significant shrinkage in tumor size while receiving the dasatinib/erlotinib combination.  The authors were able to perform direct sequencing of DDR2 in a pretreatment tumor specimen from this individual and identified a novel DDR2 kinase mutation.
This is an intriguing paper that you might well keep in mind.  Hopefully, this may stimulate other investigators to not only look for other potential genomic alterations that either drive SQC and/or represent targetable proteins but also go back and scrutinize histological and other clinicopathological characteristics of lung SQC that may have therapeutic or prognostic importance.

Posted at 11:40 AM in Lung Cancer, Lung Squamous Cell Carcinoma, Molecular Pathology, Prognostic/Predictive Cancer Markers | Permalink

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AT CRBCM WE BELIEVE

ONE OF THE MOST POWERFUL TREATMENT AGAINST A DISEASE IS TO FIND THE TARGET THAT INITIATED IT.  THE STRONGEST EVIDENCE THAT A TARGET MOLECULE IS A CRITICAL MOLECULE IS WHEN ITS MUTATION SHORTENS A LIMB IN INDIVIDUALS AND DDR2 MUTATION DOES EXACTLY THAT !!!!
It reminds me of the story of Thalidomide.  And the 2 can be linked.  I am only 50% of this! And whenever a limb is missing, your Angiogenesis and Differentiation are not very far and sure enough, Dasatinib, Imitanib and most likely Thalidomid are not far, lurking in the neighborhood!

SPONDYLO META EPIPHYSEAL DYSPLASIA (SMED) IS THE CONDITION OF SHORT STATURE AND SMALL LIMBS THAT IS RELATED TO DDR2 MUTATION!
SCIENTISTS DID NOT SLEEP, THEY LOOKED IN LUNG CANCER WHAT DASATINIB WOULD DO IN THESE PATIENTS WITH DDR2 MUTATION AND SURE ENOUGH, DASATINIB WORKS. The proof of concept is there in the pudding.

Now don't go out hunting for any short stature individual to test their gene.  But nature has given us a clue that all short stature gene found in a cancer cell, should not only tell us that the gene is targetable by an anti-VEGF and related kinase.  WE SHOULD BE TESTING ALL CANCER FOR DDR2, AND TREAT WITH DASATINIB. CURE IN THOSE CASES IS REACHABLE!  And may be we can prevent all stature with these drug.   One thing for sure, let's find DDR 2 in triple negative breast cancer, and we know what to give pronto now!