MAT1-modulated cyclin-dependent kinase-activating kinase activity cross-regulates neuroblastoma cell G1 arrest and neurite outgrowth.
Cyclin-dependent kinase-activating kinase (CAK) regulates cell cycle G1 exit, where cells commonly commit either to proliferate or to differentiate. CAK activity in G1 regulation is determined by its assembly factor and targeting subunit, ménage à trois 1 (MAT1). The precise mechanism of how proliferation/differentiation transition is induced from cancer cell G1 arrest remains unknown. We present evidence that in neuroblastoma CHP126 cells, CAK interacts with and phosphorylates retinoblastoma tumor suppressor protein (pRb) and retinoid X receptor alpha (RXRalpha). Retinoic acid (RA)-induced neuroblastoma cell proliferation/differentiation transition is associated with decreased CAK activity, as evidenced by a switch from CAK hyperphosphorylation of pRb and RXRalpha to hypophosphorylation of pRb and RXRalpha. Manipulation of MAT1 abundance shows that MAT1 reduction mimics RA-induced hypophosphorylation of pRb/RXRalpha, proliferation inhibition, and neurite outgrowth, whereas MAT1 overexpression resists these RA actions. Thus, these findings reveal an important mechanism by which MAT1-modulated CAK activity is crucial in the switch from proliferation to differentiation in neuroblastoma cells.
Zhang
Shineng
S
Department of Pathology, University of Southern California Keck School of Medicine, Los Angeles, California 90027, USA.
He
Qiaojun
Q
Peng
Hui
H
Tedeschi-Blok
Nicole
N
Triche
Timothy J
TJ
Wu
Lingtao
L
D000077556:Alitretinoin; D002454:Cell Differentiation / Q000502:physiology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D016193:G1 Phase / Q000502:physiology; D006801:Humans; D016501:Neurites / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D009447:Neuroblastoma / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D010766:Phosphorylation; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000378:metabolism; D047488:Retinoid X Receptors; D014157:Transcription Factors / Q000378:metabolism; D014212:Tretinoin / Q000494:pharmacology
D018168:Receptors, Retinoic Acid; D016160:Retinoblastoma Protein; D047488:Retinoid X Receptors; D014157:Transcription Factors; D000077556:Alitretinoin; D014212:Tretinoin