Stem cell c-KIT and HOXB4 genes: critical roles and mechanisms in self-renewal, proliferation, and differentiation.
Hematopoietic stem cells (HSCs) possess a distinct ability to perpetuate through self-renewal and to generate progeny that differentiate into mature cells of myeloid and lymphoid lineages. A better understanding of the molecular mechanisms by which HSCs replicate and differentiate from the perspective of developing new approaches for HSC transplantation is necessary for further advances. The interaction of the receptor tyrosine kinase--c-KIT--with its ligand stem cell factor plays a key role in HSC survival, mitogenesis, proliferation, differentiation, adhesion, homing, migration, and functional activation. Evidence that activating site-directed point mutations in the c-KIT gene contributes to its ligand-independent constitutive activation, which induces enhanced proliferation of HSCs, is accumulating. Similarly, and equally important, self-renewal is a process by which HSCs generate daughter cells via division. Self-renewal is necessary for retaining the HSC pool. Therefore, elucidating the molecular machinery that governs self-renewal is of key importance. The transcription factor, HOXB4 is a key molecule that has been reported to induce the in vitro expansion of HSCs via self-renewal. However, critical downstream effector molecules of HOXB4 remain to be determined. This concisely reviewed information on c-KIT and HOXB4 helps us to update our understanding of their function and mechanism of action in self-renewal, proliferation, and differentiation of HSCs, particularly modulation by c-KIT mutant interactions, and HOXB4 overexpression showing certain therapeutic implications.
Sharma
Shilpa
S
Stem-Cell Gene Therapy Research Group, Institute of Nuclear Medicine and Allied Sciences, Lucknow Road, Delhi, India-110054.
Gurudutta
Gangenahalli U
GU
Satija
Neeraj Kumar
NK
Pati
Soumya
S
Afrin
Farhat
F
Gupta
Pallavi
P
Verma
Yogesh Kumar
YK
Singh
Vimal Kishor
VK
Tripathi
R P
RP
D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D002455:Cell Division / Q000502:physiology*; D002470:Cell Survival / Q000502:physiology*; D006410:Hematopoiesis / Q000502:physiology; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000502:physiology; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D051379:Mice; D011494:Protein Kinases / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
C090460:HOXB4 protein, human; D018398:Homeodomain Proteins; C513262:Hoxb4 protein, mouse; D014157:Transcription Factors; D011494:Protein Kinases; D019009:Proto-Oncogene Proteins c-kit