Cloning and characterization of a novel intracellular protein p48.2 that negatively regulates cell cycle progression.
Neurofibromatosis type 1 (NF1) microdeletion is a large genomic deletion that embraces at least 11 continuous genes at human chromosome 17q11.2. To date, most of these genes' functions still remain undefined. In this study, we report an unknown cytokine receptor like molecule (p48.2) that is frequently deleted in patients with type-1 and type-2 NF1 microdeletions in the neurofibromin locus. The cloned gene has 1317 base pair long that encodes a 438aa intracellular protein. The gene was subsequently named p48.2 based on its predicted molecular weight. A typical fibronectin type III (FNIII) domain was identified in p48.2 between Arg(176) and Pro(261) in which a palindromic Arg-Gly-Asp (RGD) repeat plus a putative Trp-Ser-X-Trp-Ser (WSXWS) motif were found at the domain's C-terminus. p48.2 mRNAs were abundant in many tumor cell lines and normal human tissues and up-regulated in some freshly isolated lung cancer and leukemia cells. Interestingly, over-expression of p48.2 in human embryo kidney 293T cells could significantly cause G0/G1 arrest and prevented S phase entry. In contrast, repressing endogenous p48.2 gene expression by specific siRNA markedly reduced G0/G1 population. Importantly, over-expression of p48.2 could significantly up-regulate rather than down-regulate cyclin D1 and cyclin D3 expressions. We further showed that the induction of cyclin D1 expression was directly due to the activation of signal transducers and activators of transcription 3 (STAT3), but was independent of RAS/mitogen-activated protein kinase (RAS/MAPK) signaling pathway. Thus, p48.2 may represent a novel type of intracellular protein functioning as a negative regulator at the G0/G1 phase.
Yang
Fan
F
Department of Microbiology, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100005, China.
Xu
Yu-Ping
YP
Li
Jian
J
Duan
Su-Su
SS
Fu
Ying-Jie
YJ
Zhang
Yun
Y
Zhao
Yan
Y
Qiao
Wen-Tao
WT
Chen
Qi-Min
QM
Geng
Yun-Qi
YQ
Che
Chang-Yan
CY
Cao
Ying-Li
YL
Wang
Ying
Y
Zhang
Lei
L
Long
Lin
L
He
Jie
J
Cui
Quan-Cai
QC
Chen
Shu-Chang
SC
Wang
Shu-Hui
SH
Liu
Li
L
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002453:Cell Cycle / Q000235:genetics; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D003001:Cloning, Molecular; D019295:Computational Biology; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D056743:Cyclin D3 / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics; D016193:G1 Phase; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D015894:Genome, Human / Q000235:genetics; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic / Q000235:genetics; D034741:RNA, Small Interfering; D018121:Receptors, Cytokine / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D016192:Resting Phase, Cell Cycle; D050796:STAT3 Transcription Factor / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction
D018797:Cell Cycle Proteins; D056743:Cyclin D3; D034741:RNA, Small Interfering; D018121:Receptors, Cytokine; D050796:STAT3 Transcription Factor; C546289:p48.2 protein, human; D019938:Cyclin D1